Phenylacetic acid benzylamides

ABSTRACT

The present application relates to the uses of phenylacetic acid benzylamides and new (S)(+)-2-ethoxy-4-[N-[1-2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]benzoic acid and the salts thereof, which have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particularly the effect of lowering blood sugar.

This application is a continuation-in-part of Ser. No. 495,820, filedMar. 19, 1990 (U.S. Pat. No. 5,216,167), which is a continuation of Ser.No. 302,022, filed Jan. 25, 1989, now abandoned, which is acontinuation-in-part of Ser. No. 872,706, filed Jun. 10, 1986, nowabandoned, which is a continuation-in-part of Ser. No. 684,054, filedDec. 10, 1984, now abandoned, which is a continuation-in-part of Ser.No. 878,921, filed Jun. 26, 1986 (now abandoned).

This invention relates to novel phenylacetic acid benzylamides and theirnon-toxic salts, to methods of preparing these compounds, topharmaceutical compositions containing them as active ingredients, andto a method of using them as hypoglycemics.

More particularly, the present invention relates to a novel class ofcompounds represented by the formula ##STR1## wherein

R₁ represents an unbranched alkyleneimino group with 4 to 6 carbon atomsoptionally mono- or di-(alkyl of 1 to 3 carbon atoms)-substituted;

R₂ represents a hydrogen or halogen atom or a methyl or methoxy group;

R₃ represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms,a phenyl group optionally substituted by a halogen atom or a methyl ormethoxy group, an alkyl group with 1 or 2 carbon atoms substituted by ahydroxy, alkoxy, alkanoyloxy, tetrahydrofuranyl, tetrahydropyranyl,cycloalkyl or phenyl group, in which the alkoxy part can contain from 1to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3 carbon atomsand the cycloalkyl part can contain 3 to 7 carbon atoms, an alkenylgroup with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 carbonatoms, a carboxy group or an alkoxycarbonyl group with a total of 2 to 5carbon atoms;

R₄ represents a hydrogen atom, a methyl, ethyl or allyl group; and

W represents a methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl,cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl, carboxymethyl,2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylmethyl,2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group, in which eachalkoxy part can contain from 1 to 4 carbon atoms and can be substitutedby a phenyl group; and when R₃ is other then hydrogen and/or the radicalR₁ contains an optically active carbon atom, the enantiomeres and thediastereomeres thereof or their mixtures; when W is carboxyl, anon-toxic salt thereof formed with an inorganic or organic base; or anon-toxic acid addition salt thereof formed by an inorganic or organicacid with the amino function in the R₁ -position.

Specific embodiments of substituents R₁, R₂, R₃, R₄ and W are thefollowing:

R₁ : Pyrrolidino, piperidino, hexamethyleneimino, methyl-pyrrolidino,dimethyl-pyrrolidino, ethyl-pyrrolidino, 2-methyl-piperidino,3-methyl-piperidino, 4-methyl-piperidino, 3,3-dimethyl-piperidino,cis-3,5-dimethyl-piperidino, trans-3,5-dimethyl-piperidino,ethyl-piperidino, diethyl-piperidino, methyl-ethyl-piperidino,propyl-piperidino, methyl-propyl-piperidino or isopropyl-piperidino.

R₂ : Hydrogen, fluorine, chlorine, bromine, methyl or methoxy.

R₃ : Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec.butyl, tert.butyl, n-pentyl, 2-methyl-n-butyl, 3-methyl-n-butyl,2,2-dimethyl-propyl-n-hexyl, 4-methyl-n-pentyl, n-heptyl, phenyl,fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, 1-propen-1-yl,2-methyl-1-propen-1-yl, 3-methyl-2-buten-2-yl, 2-propen-1-yl,2-methyl-2-propen-1-yl, 2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 3-buten-1-yl, 2-methyl-3-buten-1-yl,3-methyl-3-buten-1-yl, 2-hexen-1-yl, 1-propyn-1-yl, 2-propyn-1-yl,2-butyn-1-yl, 2-pentyn-1-yl, hydroxymethyl, 1-hydroxy-ethyl,2-hydroxy-ethyl, methoxymethyl, ethoxymethyl, n-propoxymethyl,isopropoxymetyl, 1-methoxy-ethyl, 2-methoxy-ethyl, 1-ethoxy-ethyl,2-ethoxy-ethyl, 2-n-propoxy-ethyl, 2-isopropoxy-ethyl, acetoxymethyl,propionyloxymethyl, 1-acetoxy-ethyl, 2-acetoxy-ethyl,1-propionyloxy-ethyl, 2-propionyloxy ethyl, tetrahydrofuran-2-yl-methyl,2-(tetrahydrofuran-2-yl)-ethyl, tetrahydrofuran-3-yl-methyl,tetrahydropyran-2-yl-methyl, 2-(tetrahydropyran-2-yl)-ethyl,tetrhaydropyran-3-yl-methyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropyl-ethyl, 2-cyclobutyl-ethyl, 2-cyclopentyl-ethyl,2-cyclohexyl-ethyl, 2-cycloheptyl-ethyl, benzyl, 1-phenyl-ethyl,2-phenyl-ethyl, carboxy, emthoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec.butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl.

R₄ : Hydrogen, methyl, ethyl, n-propyl, isopropyl, allyl.

W: Methyl, hydroxymethyl, formyl, carboxy, methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec.butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl,3-phenylpropoxycarbonyl, cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl,carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,n-propoxycarbonylmethyl, n-butoxycarbonylmethyl,tert.butoxycarbonylmethyl, 2-methoxycarbonyl-ethyl,2-ethoxycarbonyl-ethyl, 2-n-propoxycarbonyl-ethyl,2-isopropoxycarbonyl-ethyl, 2-n-butoxycarbonyl-ethyl,2-tert.butoxycarbonyl-ethyl, 2-methoxycarbonyl-ethenyl,2-ethoxycarbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl or2-tert.butoxycarbonylethenyl.

One subgeneric aspect is constituted by those compounds of the formula Iwherein

R₁ represents a pyrrolidino, piperidino, 4-methyl-piperidino,3-methyl-piperidino, 3,3-dimethyl-piperidino, 3,5-dimethyl-piperidino orhexamethyleneimino group;

R₂ represents a hydrogen, fluorine or chlorine atom;

R₃ represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms,a phenyl, methyl-phenyl, chloro-phenyl, methoxy-phenyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, tetrahydrofuran-2-yl-methyl,tetrahydropyran-2-yl-methyl, propargyl, hydroxymethyl, ethoxymethyl,acetoxymethyl, propionyloxymethyl, carboxy, methoxycarbonyl,ethoxycarbonyl or propoxycarbonyl group or a branched or unbranchedalkenyl group with 3 or 4 carbon atoms;

R₄ represents a methyl, ethyl or allyl group; and

W represents a methyl, hydroxymethyl, formyl, carboxyl,benzyloxycarbonyl, carboxymethyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, cyanomethyl, 2-carboxy-ethyl,2-ethoxycarbonyl-ethyl, 2-cyano-ethyl, 2-carboxy-ethenyl,2-ethoxycarbonyl-ethenyl or 2-cyano-ethenyl group or an alkoxycarbonylgroup with 1 to 4 carbon atoms in the alkoxy part; and when R₃ is otherthen hydrogen and/or R₁ represents the 3-methyl-piperidino group, theenantiomers and the diastereomers thereof or their mixtures; when W iscarboxyl, a non-toxic salt thereof formed with an inorganic or organicbase; or a non-toxic acid addition salt thereof formed by an inorganicor organic acid with the amino function in the R₁ -position.

A preferred sugenus is constituted by those compounds of the formula Iwherein

R₁ represents a piperidino group;

R₂ represents a hydrogen atom;

R₃ represents an alkyl group with 1 to 6 carbon atoms, an alkenyl groupwith 3 or 4 carbon atoms, a phenyl, tetrahydropyran-2-yl-methyl,cyclopropylmethyl or cyclohexylmethyl group;

R₄ represents a methyl, ethyl or allyl group; and

W represents a carboxyl, methoxycarbonyl, ethoxycarbonyl or cyanomethylgroup; and

the enantiomeres thereof or their mixtures; when W is carboxyl, anon-toxic salt thereof formed with an inorganic or organic base; or anon-toxic acid addition salt thereof formed by an inorganic or organicacid with the piperidino function.

An especially preferred subgenus is constituted by those compounds ofthe formula I wherein

R₁ represents a piperidino group;

R₂ represents a hydrogen atom;

R₃ represents an alkyl group with 3 to 6 carbon atoms, an alkenyl groupwith 3 or 4 carbon atoms, a phenyl, cyclopropylmethyl orcyclohexylmethyl group;

R₄ represents a methyl or ethyl group; and

W represents a carboxyl group;

especially those compounds of the before mentioned preferred subgenus,wherein

R₃ represents an alkyl group with 3 to 6 carbon atoms, a2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohexylmethyl group; and

the enantiomers thereof or their mixtures; when W is carboxyl, anon-toxic salt thereof formed with an inorganic or organic base; or anon-toxic acid addition salt thereof for med by an inorganic or organicacid with the piperidino function.

A preferred subgenus of the before mentioned compounds are those,wherein

R₃ represents a n-propyl, n-butyl, isobutyl, sec.butyl, n-pentyl,2-methyl-1-propen-1-yl, cyclomethylpropyl or cyclohexylmethyl group,especially when

R₃ represents a n-propyl, n-butyl, isobutyl, sec.butyl or n-pentylgroup; and

the enantiomeres thereof or their mixtures; when W is carboxyl, anon-toxic salt thereof formed with an inorganic or organic base; or anon-toxic acid addition salt thereof formed by an inorganic or organicacid with the piperidino function.

According to the invention, the new compounds are obtained by thefollowing methods:

a) reacting an amine of formula ##STR2## wherein

R₁ to R₃ are defined as hereinbefore, with a carboxylic acid of formula##STR3## wherein

R₄ is defined as hereinbefore and

W' has the meanings given for W hereinbefore, in which any carboxy groupcontained in the group W can be protected by a protecting group, or withthe reactive derivatives thereof optionally prepared in the reactionmixture, if necessary with subsequent splitting off of any protectinggroup used.

Examples of reactive derivatives of a compound of formula III which canbe used include the esters thereof, such as the methyl, ethyl or benzylesters, the thioesters such as the methylthio or ethylthioesters, thehalides such as the acid chloride, the anhydrides or imidazolidesthereof.

The reaction is appropriately carried out in a solvent such as methylenechloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,dioxan, benzene, toluene, acetonitrile or dimethyl formamide, optionallyin the presence of an acid-activating agent or a dehydrating agent, e.g.in the presence of ethyl chloroformate, thionyl chloride, phsophorustrichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,

N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, or an agent which activates theamino group, e.g. phosphorus trichloride, and optionally in the presenceof an inorganic base such as sodium carbonate or a tertiary organic basesuch as triethylamine or pyridine, which can simultaneously be used assolvent, at temperatures of between -25° C. and 250° C., but preferablyat temperatures of between -10° C. and the boiling temperature of thesolvent used. The reaction can also be carried out without a solvent andfurthermore any water formed during the reaction can be removed byazeotropic distillation, e.g. by heating with toluene using a waterseparator, or by adding a drying agent such as magnesium sulphate or amolecular sieve.

If necessary, the subsequent splitting off of a protecting group ispreferably carried out by hydrolysis, conveniently either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric ortrichloroacetic acid or in the presence of a base such as sodiumhydroxide or potassium hydroxide in a suitable solvent such as water,methanol, methanol/water, ethanol, ethanol/water, water/isopropanol orwater/dioxan at temperatures of between -10° and 120° C., e.g. attemperatures of between ambient temperature and the boiling temperatureof the reaction mixture.

A tert.butyl group used as protecting group can also be split offthermally, optionally, in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran or dioxan and preferablyin the presence of a catalytic quantity of an acid such asp-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid.

Furthermore, a benzyl group used as protecting group can also be splitoff hydrogenolytically in the presence of a hydrogenation catalyst suchas palladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxan ordimethylformamide.

b) In order to prepare compounds of formula I wherein R₃ represents acarboxy or alkoxycarbonyl group and W has the meanings givenhereinbefore or W represents a carboxy, carboxmethyl, 2-carboxy-ethyl,2-carboxy-ethenyl, alkoxycarbonyl, alkoxycarbonylmethyl,2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and R₃ has themeanings given hereinbefore:

Hydrolysis, thermolysis, hydrogenolysis or alcoholysis of a compound offormula ##STR4## wherein

R₁, R₂ and R₄ are as hereinbefore defined,

B represents a bond, a methylene, ethylene or ethenylene group,

A and L each represent a nitrile group or a group which can be convertedinto a carboxy group by hydrolysis, thermolysis or hydrogenolysis and Ladditionally has the meanings given for R₃ hereinbefore.

Examples of hydrolysable groups include functional derivatives of thecarboxy group and the unsubstituted or substituted amides, esters,thioesters, ortho esters, iminoethers, amidines or anhydrides thereof,the nitrile group, the tetrazolyl group, an optionally substituted1,3-oxazxol-2-yl or 1,3-oxazolin-2-yl group,

examples of thermolytically cleavable groups include esters withtertiary alcohols, e.g. the tert.butyl ester,

examples of hydrogenolytically cleavable groups include aralkyl groups,e.g. the benzyl group, and

examples of alcoholytically cleavable groups include the cyano group.

The hydrolysis is conveniently carried out either in the presence of anacid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acidor in the presence of a base such as sodium hydroxide or potassiumhydroxide in a suitable solvent such as water, water/methanol, ethanol,water/ethanol, water/isopropanol or water/dioxan at temperatures ofbetween -10° and 120° C. , e.g. at temperatures of between ambienttemperature and the boiling temperature of the reaction mixture, and thealcoholysis of a cyano group is preferably effected in an excess of thecorresponding alcohol such as methanol, ethanol or propanol and in thepresence of an acid such as hydrochloric acid at elevated temperatures,e.g. at the boiling temperature of the reaction mixture.

If A and/or L in a compound of formula IV represents a nitrile oraminocarbonyl group, these groups can be converted into a correspondingcarboxy compound by means of 100% phosphoric acid at temperatures ofbetween 100° and 180° C., preferably at temperatures of between 120° and160° C., or with a nitrite, e.g. sodium nitride, in the presence of anacid such as sulphuric acid, the latter conveniently being used assolvent as well, as temperatures of between 0° and 50° C.

If A and/or L in a compound of formula IV represents thetert.butyloxycarbonyl group for example, the tert.butyl group can alsobe split off thermally, optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan andpreferably in the presence of a catalytic quantity of an acid such asp-toluenesulphonic, sulphuric, phosphoric or polyphosphoric acid,preferably at the boiling temperature of the solvent used, e.g. attemperatures of between 40° and 100° C.

If A and/or L in a compound of formula IV represents thebenzyloxycarbonyl group for example, the benzyl group can also be splitoff hydrogenolytically in the presence of a hydrogenation catalyst suchas palladium/charcoal in a suitable solvent such as methanol, ethanol,methanol/water, ethanol/water, glacial acetic acid, ethyl acetate,dioxan or dimethylformamide, preferably at temperatures of between 0°and 50° C., e.g. at ambient temperature and under a hydrogen pressure offrom 1 to 5 bar. During hydrogenolysis, a compound containing halogencan simultaneously be dehalogenated, any double or triple bonds presentcan be hydrogenated and any benzyloxycarbonyl group present can beconverted into a carboxy group.

c) In order to prepare compounds of formula I wherein R₄ represents ahydrogen atom:

Splitting off a protecting group from a compound of formula ##STR5##wherein

R₁ to R₃ and W are as hereinbefore defined and

R₅ represents a protecting group for a hydroxy group.

Examples of protecting groups for R₅ include, for example, an alkyl,aralkyl or trialkylsilyl group, e.g. the methyl, ethyl, propyl, allyl,benzyl or trimethylsilyl group.

Depending on the protecting group used, the protecting groups mentionedabove can be split off either by hydrolysis or by hydrogenolysis,optionally in a suitable solvent, at temperatures of between -78° and250° C.

For example, ether splitting is carried out in the presence of an acidsuch as hydrochloric, hydrobromic or sulphuric acid, boron tribromide,aluminium trichloride or pyridine hydrochloride, conveniently in asuitable solvent such as methylene chloride, glacial acetic acid orwater or in mixtures thereof at temperatures of between -78° and 250° C.The ether splitting is carried out in the presence of a proton acidconveniently at temperatures of between 0° and 150° C., preferably attemperatures of between 50° and 150° C. or with a Lewis acid preferablyin a solvent such as methylene chloride at temperatures of between -78°C. and 20° C.

For example, any protecting group used such as a benzyl group can besplit off hydrogenolytically with hydrogen in the presence of ahydrogenation catalyst such as palladium/charcoal in a suitable solventsuch as methanol, ethanol, ethanol/water, glacial acetic acid, ethylacetate, dioxan or dimethylformamide, preferably at ambient temperature,for example, and under a hydrogen pressure of from 1 to 5 bar.

d) In order to prepare compounds of formula I wherein R₄ representsmethyl, ethyl or allyl group: ##STR6## wherein

R₁ to R₃ and W are as hereinbefore defined, with a compound of formula

    X--R.sub.6                                                 (VII)

wherein

R₆ represents methyl, ethyl or allyl group

X represents a nucleophilically exchangeable group such as a halogenatom, a sulphonyloxy group or, together with the adjacent hydrogen atom,a diazo group, if R₆ represents an alkyl group with 1 to 3 carbon atoms,if necessary with subsequent hydrolysis.

The reaction is conveniently carried out with a corresponding halide,sulphonic acid ester, sulphuric acid diester or diazoalkane, e.g. withmethyl iodide, dimethyl sulphate, ethyl bromide, diethyl sulphate, allylbromide, ethyl p-toluenesulfphonate, or diazomethane, optionally in thepresence of a base such as sodium hydride, potassium carbonate, sodiumhydroxide, potassium tert.butoxide or triethylamine in a suitablesolvent such as acetone, diethylether, tetrahydrofuran, dioxan ordimethylformamide at temperatures of between 0° and 100° C., preferablyat temperatures of between 20° and 50° C.

If in a compound of formula VI R₃ represents a carboxy group and/or Wrepresents a carboxy, carboxymethyl, 2-carboxy-ethyl or2-carboxy-ethenyl group, this compound can simultaneously be convertedinto the corresponding ester compound. A compound thus obtained is, ifnecessary by cleaving the ester group, converted into the desiredcompound of formula I.

The cleaving of the ester group is carried out hydrolytically,conveniently either in the presence of an acid such as hydrochloric,sulphuric, phosphoric or trichloroacetic acid or in the presence of abase such as sodium hydroxide or potassium hydroxide in a suitablesolvent such as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxan at temperatures of between -10° and120° C., e.g. at temperatures of between ambient temperature and theboiling point of the reaction mixture.

e) In order to prepare compounds of formula I wherein W represents acyanomethyl or 2-cyano-ethyl group:

Reacting a compound of formula ##STR7## wherein

R₁ to R₄ are as hereinbefore defined,

E represents a methylene or ethylene group and

Y represents a nucleophilically exchangeable group such as a halogenatom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom ora methanesulphonyloxy or p-toluenesulphonyloxy group, with an alkalimetal cyanide such as sodium or potassium cyanide.

The reaction is conveniently carried out in a suitable solvent such asdimethylsulphoxide or dimethylformamide at temperatures of between 0°and 100° C., preferably at temperatures of between 20° and 50° C., or ina two-phase system such as methylene chloride/water in the presence of aphase transfer catalyst such as benzyl-tributyl-ammonium chloride attemperatures of between 0° and 100° C., preferably at temperatures ofbetween 20° and 50° C.

f) In order to prepare compounds of formula I wherein W represents acyanomethyl, 2-cyano-ethyl or 2-cyano-ethenyl group:

Dehydration of a compound of formula ##STR8## wherein

R₁ to R₄ are as hereinbefore defined and

G represents a methylene, ethylene or ethenylene group.

The dehydration is carried out with a water-cleaving agent such asphosphorus pentoxide, phosphorus oxychloride. triphenylphosphine/carbontetrachloride or p-toluenesulphonic acid chloride, optionally in asolvent such as methylene chloride, acetonitrile or pyridine attemperatures of between 0° and 100° C., preferably at temperatures ofbetween 20° C. and 80° C.

g) In order to prepare compounds of formula I wherein W represents a2-cyano-ethenyl, 2-carboxy-ethenyl or 2-alkoxycarbonyl-ethenyl group:

Reacting a compound of formula ##STR9## wherein

R₁ to R₄ are as hereinbefore defined, with a corresponding acetic acidderivative of formula

    Z--CH.sub.2 --Q                                            (XI)

wherein Q represents a carboxy, alkoxycarbonyl or cyano group and

Z represents a hydrogen atom, an alkoxycarbonyl, dialkylphosphono ortriphenylphosphonium halide group, optionally with subsequent hydrolysisand/or decarboxylation.

The reaction is conveniently carried out in a solvent such asdiethylether, tetrahydrofuran, 1,2-dimethoxyethane, dioxan,dimethylformamide, toluene or pyridine in the presence of a base ascondensation agent such as sodium carbonate, sodium hydride, potassiumtert.butoxide or piperidine at temperatures of between 0° and 100° C.,preferably at temperatures of between 20° and 80° C.

The subsequent hydrolysis and/or decarboxylation is conveniently carriedout either in the presence of an acid such as hydrochloric, sulphuric,phosphoric or trichloroacetic acid or in the presence of a base such assodium hydroxide or potassium hydroxide in a suitable solvent such aswater, water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxan at temperatures of between -10° C. and 120° C., e.g. attemperatures of between ambient temperature and the boiling temperatureof the reaction mixture.

h) In order to prepare compounds of formula I wherein W represents a2-carboxy-ethyl, 2-alkoxycarbonyl-ethyl or 2-cyano-ethyl-group:

Reduction of a compound of formula ##STR10## wherein

R₁ to R₄ are as hereinbefore defined and

W" represents a 2-carboxy-ethenyl, 2-alkoxycarbonyl-ethenyl or2-cyano-ethenyl group.

The reduction is preferably carried out in a suitable solvent such asmethanol, ethanol, isopropanol, ethyl acetate, dioxan, tetrahydrofuran,dimethylformamide, benzene or benzene/ethanol with hydrogen in thepresence of a suitable hydrogenation catalyst such aspalladium/charcoal. Raney nickel ortris-#[triphenylphosphine#*-rhodium(I)chloride at temperatures ofbetween 0° and 100° C., but preferably at temperatures of between 20° C.and 50° C., under a hydrogen pressure of from 1 to 5 bar or, if W"contains a cyano group, with nascent hydrogen, e.g. withmagnesium/methanol, or with a copper hydride complex, e.g. with thecomplex prepared from copper bromide, sodiumbis(2-methoxyethoxy)-aluminium hydride and sec.butanol at temperaturesof between -78° and 50° C. Other groups can be reduced at the same time,e.g. a benzyloxy group can be reduced to the hydroxy group, an alkenylor alkynyl group can be reduced to the corresponding alkyl group or aformyl group can be reduced to the hydroxymethyl group, or they can bereplaced by hydrogen atoms, e.g. a halogen atom can be replaced by ahydrogen atom.

i) In order to prepared compounds of formula I wherein R₃ represents analkyl group with 1 to 2 carbon atoms substituted by an alkyloxy oralkanoyloxy group:

Reacting a compound of formula ##STR11## wherein

R₁, R₂, R₄ and W are as hereinbefore defined and R₃ ' represents analkyl group with 1 to 2 carbon atoms substituted by a hydroxy group,with a compound of formula

    U--R.sub.7                                                 (XIV)

wherein

R₇ represents an alkyl group with 1 to 3 carbon atoms or an acetyl orpropionyl group and

U represents a nucleophilically exchangeable group such as a halogenatom, a sulphonyloxy group, an acetoxy or propionyloxy group or,together with the adjacent hydrogen atom, represents a diazo group if R₇represents an alkyl group with 1 to 3 carbon atoms, optionally withsubsequent hydrolysis.

The reaction is conveniently carried out with a corresponding halide,anhydride, sulphonic acid ester, sulphuric acid diester or diazoalkane,e.g. with methyl iodide, dimethyl sulphate, ethyl iodide, diethylsulphate, n-propyl iodide, isopropyl bromide, acetyl chloride, acetichydride, propionic acid chloride, propionic acid anhydride, ethylp-toluenesulphonate or isopropylmethanesulphonate, optionally in thepresence of a base such as sodium hydride, potassium carbonate, sodiumhydroxide, potassium tert.butoxide or triethylamine, or withdiazomethane, optionally in the presence of a Lewis acid, e.g. borontrifluoride, preferably in a suitable solvent such as acetone,diethylether, tetrahydrofuran, dioxan, pyridine or dimethylformamide attemperatures of between 0° and 100° C., preferably at temperatures ofbetween 20° and 50° C., in which an anhydride used as the acylatingagent can simultaneously also be used as solvent.

If in a compound of formula XIII W represents a carboxy, carboxymethyl,2-carboxy-ethyl or 2-carboxy-ethenyl group and/or R₄ represents ahydrogen atom, this can simultaneously be converted into thecorresponding ester and/or ether compound.

k) In order to prepare compounds of formula I wherein R₃ represents analkoxycarbonyl group:

Reacting a compound of formula ##STR12## wherein

R₁, R₂, R₄ and W are as hereinbefore defined and

R₃ represents a hydrogen atom or alkali metal atom, or the reactivederivatives thereof optionally prepared in the reaction mixture, with acompound of formula

    T--R.sub.9                                                 (XVI)

wherein

R₉ represents an alkyl group with 1 to 4 carbon atoms and

T represents a hydroxy group or a nucleophilically exchangeable groupsuch as a halogen atom or a sulphonyloxy group, or together with theadjacent hydrogen atom of the group R₉ represents a diazo group,optionally followed by hydrogenolysis if W contains a benzyloxycarbonylgroup.

An example of a reactive derivative of a compound of formula XV is theimidazolide thereof.

The reaction is conveniently carried out in the corresponding alcohol assolvent or in a suitable solvent such as methylene chloride, chloroform,ether, tetrahydrofuran, dioxan, dimethylformamide, benzene or toluene,optionally in the presence of an acid-activating agent or a dehydratingagent, e.g. in the presence of hydrogen chloride, sulphuric acid, ethylchloroformate, thionylchloride, carbon tetrachloride/triphenylphosphine,carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or the isoureaethers thereof, optionally in the presence of a reaction acceleratorsuch as copper chloride and optionally in the presence of an inorganicbase such as potassium carbonate or a tertiary organic base such astriethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene or pyridine, or bytransesterification, e.g. with a corresponding carbonic acid diester, attemperatures of between -20° C. and 100° C., but preferably attemperatures of between -10° C. and the boiling temperature of thesolvent used.

The optional subsequent hydrogenolysis is carried out in the presence ofa hydrogenation catalyst such as palladium/charcoal in a suitablesolvent such as methanol, ethanol, ethanol/water, glacial acetic acid,ethyl acetate, dioxan or dimethylformamide.

If W in a compound of formula XV contains a carboxy group, this can beconverted during the reaction into the corresponding alkoxycarbonylgroup.

l) In order to prepare compounds of formula I wherein

R₄ represents a hydrogen, atom, methyl, ethyl or allyl group and

W represents a methyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl,alkoxycarbonyl, alkoxycarbonylmethyl or 2-alkoxycarbonylethyl group, inwhich the alkoxy part can contain from 1 to 4 carbon atoms.

Reacting a compound of formula ##STR13## wherein

R₁ and R₂ are as hereinbefore defined and

R₃ " represents a hydrogen atom, an alkyl group with 1 to 7 carbonatoms, a phenyl group optionally substituted by a halogen atom or by amethyl or methoxy group, an alkyl group with 1 or 2 carbon atomssubstituted by an alkoxy, alkanoyloxy, tetrahydrofuranyl,tetrahydropyranyl, cycloalkyl or phenyl group, wherein the alkoxy partcan contain 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3carbon atoms and the cycloalkyl part can contain 3 to 7 carbon atoms, analkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5carbon atoms, a carboxy group or an alkoxycarbonyl group with a total of2 to 5 carbon atoms, with a compound of formula ##STR14## wherein

R₄ is as hereinbefore defined and

W"' represents a methyl, formyl, carboxy, carboxymethyl,2-carboxy-ethyl, alkoxycarbonyl, alkoxy-carbonylmethyl or2-alkoxy-carbonyl-ether group, in wich each alkoxy part can contain from1 to 4 carbon atoms.

The reaction is carried out in the presence of a strong acid which cansimultaneously serve as solvent, preferably in concentrated sulfuricacid, at temperatures of between 0° and 150° C., preferably attemperatures of between 20° and 100° C.

If in a compound of formula XVIII R₄ represents an allyl group, this issplit off during the reaction or after the reaction by the addition ofwater.

m) In order to prepare compounds of formula I wherein

R₄ represents a hydrogen atom, a methyl or ethyl group,

R₃ represents an alkyl group with 1 to 7 carbon atoms, a phenyl groupoptionally substituted by a methyl or methoxy group, an alkyl group with1 or 2 carbon atoms substituted by an alkoxy, tetrahydrofuranyl,tetrahydropyranyl, cycloalkyl or phenyl group in which the alkoxy partcan contain 1 to 3 carbon atoms and the cycloalkyl part can contain 5 to7 carbon atoms, and

W represents a methyl, hydroxymethyl, carboxy, cyanomethyl,2-cyano-ethyl, carboxymethyl, 2-carboxy-ethyl, alkoxycarbonyl,alkoxycarbonyl-methyl or 2-alkoxycarbonyl-ethyl group in which thealkoxy part can contain from 1 to 4 carbon atoms.

Reduction of a compound of formula ##STR15## wherein

R₁, R₂ and R₄ are as hereinbefore defined and

D represents a group of formula ##STR16## in which

R₃ "' represents a phenyl group optionally substituted by a halogen atomor by a methyl or methoxy group,

R₁₀ and R₁₁ together with the carbon atom between them represents analkylidene group with 1 to 7 carbon atoms, an alkylidene group with 1 or2 carbon atoms substituted by an alkoxy, tetrahydrofuranyl,tetrahydropyranyl, cycloalkyl or phenyl group, in which the alkoxy partcan contain 1 to 3 carbon atoms and the cycloalkyl part can contain 5 to7 carbon atoms, and

W"" represents a methyl, hydroxymethyl, formyl, carboxy, cyanomethyl,2-cyano-ethyl, 2-cyano-ethyl, carboxymethyl, 2-carboxy-ethyl,2-carboxy-ethenyl, alkoxycarbonyl, alkoxycarbonylmethyl,2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl group, in which thealkoxy part can contain from 1 to 4 carbon atoms and can be substitutedby a phenyl group.

The reduction is preferably carried out with hydrogen in the presence ofa hydrogenation, catalyst such as palladium/charcoal or Raney-nickel ina suitable solvent such as methanol, ethanol, isopropanol, ethylacetate, dioxan, tetrahydrofuran, dimethylformamide, benzene orbenzene/ethanol at temperatures of between 0° and 100° C., preferably attemperatures of between 20° and 50° C., and under a hydrogen pressure offrom 1 to 5 b ar. When a suitable chiral hydrogenation catalyst is used,such as a metal ligand complex e.g. [(2S),(4S)-1-tert.butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine-rhodium-cyclooctadiene(1,5)]-perchlorate,the addition of hydrogen occurs enantioselectively. Moreover, in thecatalytic hydrogenation, other groups can also be reduced, e.g. abenzyloxy group can be reduced to the hydroxy group or a formyl groupcan be reduced to the hydroxy methyl group, or they can be replaced byhydrogen atoms, e.g. a halogen atom can be replaced by a hydrogen atom.

If a compound of the formula I is obtained wherein R₂ is halogen and/orR₃ is halophenyl and/or W is hydroxymethyl which has been converted intohalomethyl, it may, if desired, be converted by de-halogenation into acorresponding compound of the formula I wherein R₂ is hydrogen and/or R₃is phenyl and/or W is methyl.

If a compound of the formula I is obtained wherein W is carboxyl, thiscompound may, if desired, by converted by esterification into acorresponding compound of the formula I wherein W is alkoxycarbonyl orphenylalkoxycarbonyl.

If a compound of the formula I is obtained wherein W is carboxyl,alkoxycarbonyl or phenylalkoxycarbonyl, this compound may be convertedby reduction into a corresponding compound of the formula I wherein W isformyl or hydroxymethyl.

If a compound of the formula I is obtained wherein W is hydroxymethyl,this compound may be converted by oxidation into a correspondingcompound of the formula I wherein W is formyl or carboxyl.

If a compound of the formula I is obtained wherein W is carboxyl, thiscompound may be converted, via a sulfonic acid hydrazide and subsequentdisproportionation, into a corresponding compound of the formula Iwherein W is formyl.

The subsequent dehalogenation is advantageously carried out by catalytichydrogenation, for example with palladium-on-charcoal, in a suitablesolvent such as methanol, ethanol, tetrahydrofuran, dioxane,dimethylformamide or ethyl acetate, optionally in the presence of a basesuch as triethylamine, and at temperatures between 20° and 100° C.,preferably at 20° to 50° C.

The subsequent esterification is advantageously carried out in asuitable solvent, for instance in a corresponding alcohol, pyridine,toluene, methylene chloride, tetrahydrofuran or dioxane, in the presenceof an acid-activating and/or dehydrating agent such as thionyl chloride,ethyl chloroformate, carbonyldiimidazole orN,N'-dicyclohexylcarbodiimide or the isourea ethers thereof, optionallyin the presence of a reaction accelerator such as copper chloride, or bytrans-esterification, for instance with a corresponding carbonic aciddiester, at temperatures between 0° and 100° C., but preferably attemperatures between 20° and the boiling point of the solvent which isused.

The subsequent reduction is preferably carried out with a metal hydride,for example with a complex metal hydride such as lithium aluminumhydride, lithium borohydride or lithium borohydride/trimethylborate, ina suitable solvent such as diethyl ether, tetrahydrofuran, dioxane or1,2-dimethoxyethane at temperatures between 0° and 100° C., butpreferably at temperatures between 20° C. and 60° C.

The subsequent oxidation of an alcohol is preferably carried out with anoxidizing agent, for instance with pyridinium chlorochromate ormanganese dioxide, in a suitable solvent such as chloroform or methylenechloride at temperatures between -10° C. and 50° C., but preferably attemperatures between 0° and 20° C.

The subsequent disproportionation of a sulfonic acid hydrazide, obtainedby reacting a corresponding hydrazine with a suitable reactivecarboxylic acid derivative, is carried out in the presence of a basesuch as sodium carbonate in a solvent such as ethylene glycol attemperatures between 100° C. and 200° C., but preferably at 160°-170° C.

If according to the invention a racemic compound of formula I isobtained wherein R₃ has the meanings given hereinbefore with theexception of the hydrogen atom, this compound can be resolved into theenantiomers thereof via the diastereomeric adducts, complexes, salts orderivatives thereof.

The subsequent racemate splitting is preferably carried out by column orHPL chromatography by forming diastereomeric adducts or complexes in achiral phase.

The compounds of formula I obtained according to one invention can alsobe converted into the salts thereof and, for pharmaceutical use, intothe nontoxic, pharmaceutically acceptable salts thereof with inorganicor organic acids or bases. Suitable acids include, for example,hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric,tartaric, succinic, maleic, fumaric, aspartic or glutamic acid andsuitable bases include sodium hydroxide, potassium hydroxide, calciumhydroxide, cyclohexylamine, ethanolamine, diethanolamine,triethanolamine, ethylenediamine, lysine or arginine.

The compounds of formulae II to XIX used as starting materials are knownfrom the literature in some cases or can be obtained by methods knownper se.

Thus, for example, a compound of formula II is obtained by reducing acorresponding nitrile with lithium aluminium hydride or withcatalytically activated hydrogen, by reacting a corresponding nitrilewith a corresponding grignard or lithium compound and subsequentlithium-aluminium hydride reduction or subsequent hydrolysis to form theketime which is subsequently reduced with catalytically activatedhydrogen, with a complex metal hydride or with nascent hydrogen, byhydrolysis or by hydrazinolysis of a corresponding phthalimido compound,by reacting a corresponding ketone with ammonium formate and subsequenthydrolysis or with an ammonium salt in the presence of sodiumcyanoborohydride, by reduction of a corresponding oxime with lithiumaluminium hydride, with catalytically activated or nascent hydrogen, byreduction of a corresponding N-benzyl or N-1-phenylethyl Schiff's basee.g. with a complex metal hydride in ether or tetrahydrofuan attemperatures of between -78° C. and the boiling temperature of thesolvent used with subsequent splitting off of the benzyl or1-phenylethyl group by catalytic hydrogenation, by lithiation of acorresponding benzylideneimino-benzyl compound, e.g. by means oflithium-diisopropylamide at temperatures of between -78° and 20° C.,subsequent reaction with a corresponding halogen compound, e.g., with acorresponding bromoalkyl, bromoalkenyl or bromoalkinyl compound, andsubsequent hydrolysis, by Ritter reaction of a corresponding alcoholwith potassium cyanide in sulfuric acid, by Hofmann, Curtius, Lossen orSchmidt degradation of a corresponding compound or by converting acorresponding benzaldehyde into a corresponding glycine derivative, e.g.using sodium cyanide/ammonium carbonate in ethanol/water into acorresponding hydantoin derivative, hydrolysis thereof, and, ifnecessary, subsequent esterification and, if necessary, subsequentreduction, e.g. with a complex metal hydride in ether ortetrahydrofuran.

An amine of formula II thus obtained having a chiral centre can beresolved into its enantiomers by racemate splitting, e.g. by fractionalcrystallization of the diastereomeric salts with optically active acidsand subsequent decomposition of the salts or by column or HPLchromatography, optionally in the form of the acyl derivative thereof,or by forming diasteromeric compounds, separating them and subsequentlysplitting them.

Moreover, an optically active amine of formula II can also be preparedby enantioselective reduction of a corresponding ketimine using complexboron or aluminium hydrides in which some of the hydride hydrogen atomshave been replaced by optically active alkoxide groups, or by means ofhydrogen in the presence of a suitable chiral hydrogenation catalyst oranalogously starting from a corresponding N-benzyl orN-(1-phenethyl)-ketimine or from a corresponding N-acyl-ketimine orenimide and optionally subsequently splitting off the benzyl,1-phenethyl or acyl group.

Furthermore, an optically active amine of formula II can also beprepared by diastereoselective reduction of a corresponding ketimine orhydrazone substituted at the nitrogen atom with a chiral group, using acomplex or non-complex boron or aluminium hydride in which some of thehydride hydrogens can optionally be replaced by corresponding alkoxide,phenoxide or alkyl groups or using hydrogen in the presence of asuitable hydrogenation catalyst optionally with subsequent splitting offof the chiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

Moreover, an optically active amine of formula II can also be preparedby diastereo-selective addition of a corresponding organometalliccompound, preferably a grignard or lithium compound, to a correspondingaldimine substituted with a chiral group at the nitrogen atom, bysubsequent hydrolysis and optionally subsequent splitting off of thechiral auxiliary group by catalytic hydrogenolysis or hydrolysis.

The compounds of formulae IV, V, VI, VIII, IX, X, XII, XIII and XV usedas starting materials are obtained by reacting a corresponding aminewith a suitable carboxylic acid or a reactive derivative thereof and, ifnecessary, subsequently splitting off any protecting group used.

A compound of formula XVII used as starting material is obtained byreducing a corresponding carbonyl compound by reacting a correspondingcarbonyl compound with a corresponding grignard or lithium reagent or byhydrolysis or alcoholysis of a corresponding cyanohydrin and, ifnecessary, subsequent esterification.

A compound of formula XIX used as starting material is obtained byacylating a corresponding ketimine or the organometallic complex thereofwith a corresponding carboxylic acid or reactive derivatives thereof,optionally with tautomerization.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form A); dissolved in methylene chloride (IR)

FIG. 2:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form B); dissolved in methylene chloride (IR)

FIG. 3:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form C); dissolved in methylene chloride (IR)

FIG. 4:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form A); solid form (IR)

FIG. 5:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form B); solid form (IR)

FIG. 6:2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form C); solid form (IR)

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 1 Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}aminocarbonylmethyl]-benzoate

2 g (7.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 2.46 g(9.38 mmols) of triphenylphosphine, 1.7 ml (12.3 mmols) of triethylamineand 0.76 ml (7.9 mmols) of carbon tetrachloride were added to a solutionof 1.84 g (7.9 mmols) of 1-(2-piperidinophenyl)-1-butylamine in 19 ml ofacetronitrile, and the mixture was stirred for two days at roomtemperature. It was then evaporated in vacuo, and the residue was takenup in a mixture of ethyl acetate and water. The organic phase was driedfiltered and evaporated in vacuo. The evaporation residue was purifiedby column chromatography on silica gel (toluene/acetone=5/1).

Yield: 3 g (81% of theory).

M.p. 113°-115° C. (petroleum ether).

Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.18%; H-8.27%;N-6.16%.

The following compounds were prepared by a procedure analogous to thatdescribed in Example 1:

(a) Methyl2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and3-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 78% of theory.

M.p. 92°-85° C.

Calculated: C-70/22%; H-7.37%; N-6.82%. Found: C-70.54%; H-7.49%;N-6.75%.

(b) Ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 77% of theory.

M.p. 149°-151° C.

Calculated: C-74.37%; H-7.25%; N-5.60%. Found: C-74.69%; H-7.44%;N-5.59%.

(c) Methyl2-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzylamine and3-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 65% of theory.

M.p. 189°-190° C.

Calculated: C-73.07%; H-6.83%; N-5.93%. Found: C-73.51%; H-6.75%;N-5.86%.

(d) Ethyl2-ethoxy-4-[N-1-{2-piperidino-phenyl}-1-ethyl)aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 69% of theory.

M.p. 92°-93° C.

Calculated: C-71.21%; H-7.81%; N-6.395. Found: C-71.29%; H-8.03%;N-6.58%.

(e) Ethyl2-ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(5-chloro-2-piperidino-phenyl)-1-propylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 80% of theory.

M.p. 110°-112° C.

Calculated: C-66.58%; H-7.24%; N-5.75%; Cl-7.28%. Found: C-66.61%;H-7.34%; N-5.86%: Cl-71.35%.

(f) Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-pentylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 63% of theory.

M.p. 113°-115° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.66%; H-8.26%;N-5.99%.

(g) Ethyl2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-pyrrolidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 50% of theory.

M.p. 85°-87° C.

Calculated: C-71.65%; H-8.02%; N-61.19%. Found: C-71.90%; H-8.37%;N-6.34%.

(h) Ethyl2-ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-[2-(4-methyl-piperidino)-phenyl]-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 44% of theory.

M.p. 127°-128° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.20%; H-8.23%;N-5.69%.

(i) Ethyl2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-hexamethyleneimino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 44% of theory.

M.p. 97°-100° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.41%; H-8.50%;N-5.66%.

(k) Ethyl2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(4-methyl-2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 68% of theory.

M.p. 113°-114° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.36%; H-8.31%;N-5.91%.

(l) Ethyl2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(6-methyl-2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 62% of theory.

M.p. <20° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.30%; H-8.50%;N-5.72%.

(m) Ethyl 2-ethoxy-4-[N-{1-(6-chloro-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(6-chloro-2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 85% of theory.

M.p. <20° C.

Calculated: C-67.12%; H-7.44%; N-5.50%; Cl-7.08%. Found: C-67.70%;H-7.77%; N-5.92%; Cl-7.24%.

(n) Ethyl2-ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(4-methoxy-2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 65% of theory.

M.p. 109°-110° C.

Calculated: Mol. peak m/e=496 Found: Mol. peak m/e=496

(o) Ethyl2-ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate

Prepared from 1-(5-methoxy-2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 31% of theory.

M.p. 117°-120° C.

Calculated: Mol. peak m/e=496 Found: Mol. peak m/e=496

(p) Ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.

Yield: 46% of theory.

M.p. 133°-134° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.08%; H-7.91%;N-6.45%.

(q) Methyl2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and3-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 67% of theory.

M.p. 128°-131° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.46%; H-7.80%;N-6.07%.

(r) n-Propyl2-n-propoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and3-n-Propoxy-4-n-propoxycarbonyl-phenylacetic acid.

Yield: 56% of theory.

M.p. 88°-89° C.

Calculated: C-72.84%; H-8.56%; N-5.66%. Found: C-72.80%; H-8.78%;N-5.78%.

(s) Ethyl2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]benzoate

Prepared from 5-chloro-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 65% of theory.

M.p. 106°-108° C.

Calculated: C-65.41%; H-6.81%; N-6.10%; Cl-7.73%. Found: C-65.81%;H-6.89%; N-6.11%; Cl-7.62%.

(t) Ethyl(-)-2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from (-)-α-phenyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 87% of theory.

M.p. 110°-111° C.

Calculated: mol peak m/e=500 Found: mol peak m/e=500

Specification rotation: [α]_(D) ²⁰ -6.3° (c=1, methanol).

(u) Ethyl2-ethoxy-4-[N-(6-methyl-α-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate

Prepared from 6-methyl-α-phenyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 39% of theory.

M.p. <20° C.

Calculated: C-74.68%; H-7.44%; N-5.44%. Found: C-74.81%; H-7.56%;N-5.32%.

(v) Ethyl2-ethoxy-4-[N-{α-(4-methyl-phenyl)-2-piperidinobenzyl}-aminocarbonylmethyl]-benzoate

Prepared from α-(4-methyl-phenyl)-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 34% of theory.

M.p. 150°-152° C.

Calculated: C-74.68%; H-7.44%; N-5.44%. Found: C-74.71%; H-7.51%;N-5.29%.

(w) Ethyl2-ethoxy-4-[N-(α-phenyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-pyrrolidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 45% of theory.

M.p. 85°-87° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-73.95%; H-7.07%;N-5.70%.

(x) Methyl2-methoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)-aminocarbonylmethyl)-benzoate

Prepared from 2-hexamethyleneimino-α-phenyl-benzylamine and3-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 45% of theory.

M.p. 181°-183° C.

Calculated: C-74.05%; H-7.04%; N-5.74%. Found: C-74.09%; H-6.62%;N-5.74%.

(y) Ethyl2-ethoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)aminocarbonylmethyl]-benzoate

Prepared from 2hexamethyleneimino-α-phenyl-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 41% of theory.

M.p. 140°-141° C.

Calculated: C-74.68%; H-7.44%; N-5.44%. Found: C-74.66%; H-7.62%;N-5.45%.

(z)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-toluene

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-methyl-phenylacetic acid.

Yield: 55% of theory.

M.p. 107°-108° C.

Calculated: C-76.43%; H-8.88%; N-6.86%. Found: C-76.36%; H-8.99%;N-6.97%.

(aa) Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-heptylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 79% of theory.

M.p. 101°-104° C.

Calculated: C-73.19%; H-8.72%; N-5.51%. Found: C-73.00%; H-8.90%;N-5.28%.

EXAMPLE 2 Ethyl(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

0.90 g (3.57 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid and0.61 g (3.73 mmol) of N,N'-carbonyldiimidazole are refluxed for 5 hoursin 9 ml of absolute tetrahydrofuran. Then a solution of 0.85 g (3.67mmol) of (+)-1-(2-piperidinophenyl)-1-butylamine (ee=94.2) in 9 ml ofabsolute tetrahydrofuran is added and the mixture is refluxed for 3hours. It is concentrated in vacuo and the evaporation residue isdistributed between chloroform and water. The organic phase is dried,filtered and evaporated in vacuo. The evaporated extract is purified bycolumn chromatography on silica gel (toluene/acetone=10.1).

Yield: 0.85 g (51.2% of theory).

M.p. 118°-119° C. (petroleum ether/toluene=50/2).

Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.43%; H-8.34%;N-6.00%.

Specification rotation: [α]_(D) ²⁰ =+7.1° (c=1.06 in methanol).

The following compounds were obtained analogously to Example 2:

(a) Methyl3-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and2-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 89of theory.

M.p. 102°-105° C.

Calculated: C-71.20%; H-7.81%; N-6.39%. Found: C-71.20%; H-8.02%;N-6.27%.

(b) Ethyl3-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 73% of theory.

M.p. 136°-138° C.

Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.50%; H-8.33%;N-5.95%.

(c) Ethyl3-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonbylmethyl]-benzoate

Prepared from 1-(4-methyl-2-piperidino-phenyl)-1-butylamine and2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 61% of theory.

M.p. 108°-110° C.

Calculated: C-72.46%; H-8.39%; N-5.83%. Found: C-72.50%; H-8.46%;N-5.92.

(d) Ethyl3-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(6-methyl-2-piperidino-phenyl)-1-butylamine and2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 90% of theory.

M.p. <20° C.

Calculated: C-72.46%; H-8.39%; N-5.83%. Found: C-72.86%; H-8.20%;N-5.50%.

(e) Methyl3-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzylamine and2-methoxy-4-methoxycarbonyl-phenylacetic acid.

Yield: 86% of theory.

M.p. 144°-148° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.70%; H-6.85%;N-5.84%.

(f) Ethyl3-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzylamine and2-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Yield: 77% of theory.

M.p. 112°-115° C.

Calculated: C-74.37%; H-7.25%; N-5.60%. Found: C-74.69%; H-7.29%;N-5.75%.

EXAMPLE 3 Ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

A solution of 4.7 g (20 mmol) of ethyl 2-ethoxy-4-cyanomethyl-benzoateand 5.3 g (20 mmol) of α-phenyl-2-piperidino-benzyl alcohol in 30 ml of0-dichlorobenzene was added dropwise at 22°-23° C. to a mixture of 30 mlof concentrated sulfuric acid and 30 ml of o-dichlorobenzene. Themixture was stirred for 2 hours at room temperature. Then, theo-dichlorobenzene phase was separated, and the residue was added to ice.After the aqueous mixture had been made alkaline with a soda solution,it was extracted with chloroform. The extracts were dried over magnesiumsulfate and concentrated by evaporation. The residue was triturated withpetroleum ether (30°-60°), filtered off and purified on silica gel(toluene/ethylacetate=5:1) by column chromatography.

Yield: 5.6 g (56% of theory).

M.p. 150°-151° C.

Calculated: C-74.37%; H-7.25%; N-5.60%. Found: C-74.59%; H-7.41%;N-5.45%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 3:

(a) Methyl2-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzyl alcohol and methyl4-cyanomethyl-2-methoxy-benzoate.

Yield: 34% of theory.

M.p. 189°-191° C.

Calculated: C-73.70%; -6.83%; N-5.93%. Found: C-73.63%; H-7.05%;N-5.95%.

(b)2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from α-phenyl-2-piperidino-benzyl alcohol and2-ethoxy-4-cyanomethyl-benzoic acid.

Extraction at pH 5.

Yield: 47% of theory.

M.p. 154°-155° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.61%; H-6.72%;N-5.65%.

(c)2-Methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from α-phenyl-2-piperidino-benzyl alcohol and4-cyanomethyl-2-methoxy-benzoic acid.

Extraction at pH 5.

Yield: 30% of theory.

M.p. 202°-204° C.

Calculated: C-73.43%; H-6.59%; N-6.11%. Found: C-73.17%; H-6.41%;N-6.05%.

(d) Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-butanol andethyl-2-ethoxy-4-cyanomethyl benzoate.

Yield: 5% of theory.

M.p. 112°-114° C.

Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.29%; H-8.46%;N-6.31%.

(e) Methyl2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-ethanol and methyl4-cyanomethyl-2-methoxy-benzoate.

Yield: 18% of theory.

M.p. 83°-85° C.

Calculated: C-70.22%; H-7.37%; N-6.82%. Found: C-70.60%; H-7.29%;N-6.97%.

(f)2-Methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoicacid

Prepared from 1-(2-piperidino-phenyl)-1-ethanol and4-cyanomethyl-2-methoxy-benzoic acid.

Extraction at pH 5.5.

Yield: 21% of theory.

M.p. 118°-120° C.

Calculated: m/e=396 Found: m/e=396.

(g) Ethyl2-ethoxy-4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate

Prepared from 4-methyl-α-phenyl-2-piperidino-benzyl alcohol and ethyl2-ethoxy-4-cyanomethyl-benzoate.

Yield: 45% of theory.

M.p. 124°-125° C.

Calculated: C-74.68%; H-7.44%; N-5.44%. Found: C-74.81%; H-7.56%;N-5.32%.

(h) Methyl2-methoxy-4-[N-{α-(4-chloro-phenyl)-2-piperidino-benzyl}-aminocarbonylmethyl]-benzoate

Prepared from α-(4-chlorophenyl)-2-piperidino-benzyl alcohol and methyl2-methoxy-4-cyanomethyl-benzoate.

Yield: 47% of theory.

M.p. 176°-178° C.

Calculated: C-68.70%; H-6.17%; N-5.53%; Cl-6.99%. Found: C-69.05%;H-5.93%; N-5.76%; Cl-7.10%.

(i) Ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzyl alcohol and ethyl4-cyanomethyl-2-hydroxy-benzoate.

Yield: 78% of theory.

M.p. 172°-174° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.80%; H-6.81%;N-5.83%.

(k) n-Propyl2-n-propoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from α-phenyl-2-piperidino-benzyl alcohol and n-propyl4-cyanomethyl-2-n-propoxy benzoate.

Yield: 52% of theory.

M.p. 119°-120° C.

Calculated: C-74.97%; H-7.63%; N-5.30%. Found: C-74.91%; H-7.72%;N-5.25%.

EXAMPLE 42-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

A mixture of 2 g (4.3 mmols) of ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoateand 5.3 ml of 1N sodium hydroxide solution in 20 ml of ethanol wasstirred for 3 hours at 60° C., then neutralized with 5.3 ml of 1Nhydrochloric acid, and the ethanol was evaporated in vacuo. The residuewas taken up in a mixture of ethyl acetate and water, and the organicphase was dried, filtered and evaporated in vacuo. The evaporationresidue was crystallized from petroleum ether with the addition ofethanol.

Yield: 1.3 g (69% of theory).

M.p. 88°-90° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.62%; H-7.73%;N-6.54%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 4:

(a)2-Methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoicacid×0.67 H₂ O

Prepared from methyl2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoate.

Yield: 60% of theory.

M.p. 116°-120° C.

Calculated: C-67.62%; H-7.07%; N-6.85%. Found: C-67.70%; H-6.87%;N-6.55%.

(b)2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 89% of theory.

M.p. 155°-156° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.60%; H-6.96%;N-6.12%.

(c)2-Methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl)-benzoicacid

Prepared from methyl2-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 68% of theory.

M.p. 202°-204° C.

Calculated: C-73.34%; H-6.59%; N-6.11%. Found: C-73.60%; H-6.77%;N-6.20%.

(d)2-Ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate.

Yield: 74% of theory.

M.p. 115°-118° C.

Calculated: C-65.42%; H-6.81%; N-6.10%; Cl-7.72%. Found: C-65.54%;H-6.94%: N-5.81%; Cl-7.89%.

(e)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-propyl)-aminocarbonylmethyl]-benzoate.

Yield: 73% of theory.

M.p. 81°-83° C.

Calculated: C-70.73%; H-7.60%; N-6.60%. Found: C-70.90%; H-7.47%;N-6.77%.

(f)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoate.

Yield: 92% of theory.

M.p. 82°-85° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.45%; H-8.01%;N-6.13%.

(g)2-Ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 77% of theory.

M.p. 120°-123° C.

Calculated: C-70.73%; H-7.60%; N-6.60%. Found: C-70.71%; H-7.44%;N-6.33%.

(h)2-Ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-(4-methyl-piperidino)-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 71% of theory.

M.p. 83°-85° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.60%; H-7.94%;N-6.09%.

(i)2-Ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 81% of theory.

M.p. 101°-105° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.31%; H-7.79%;N-6.18%.

(k)2-Ethoxy-4-[N-{1-(6-chloro-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(6-chloro-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 82% of theory.

M.p. 133°-136° C.

Calculated: C-66.02%; H-7.03%; N-5.92%; Cl-7.50%. Found: C-66.48%;H-7.47%; N-5.98%; Cl-7.88%.

(l)2-Ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(4-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 81% of theory.

M.p. 98°-100° C.

Calculated: C-69.21%; H-7.47%; N-5.98%. Found: C-69.12%; H-7.62%;N-5.78%.

(m)2-Ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(5-methoxy-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 74% of theory.

M.p. 145°20 -148° C.

Calculated: C-69.21%; H-7.74%; N-5.98%. Found: C-69.00%; H-7.65%;N-5.89%.

(n)2-Methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from methyl2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 86% of theory.

M.p. 140°-143° C.

Calculated: C-70.73%; H-7.60%; N-6.60%. Found: C-70.49%; H-7.58%;N-6.31%.

(o)2-n-Propoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from n-propyl2-n-propoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 89% of theory.

M.p. 128°-132° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.40%; H-7.90%;N-6.47%.

(p)2-Ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid×0.5 H₂ O

Prepared from ethyl2-ethoxy-4-[N-5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 93% of theory.

M.p. 153°-155° C.

Calculated: C-62.79%; H-6.41%; N-6.36%; Cl-8.06%. Found: C-63.21%;H-6.34%; N-5.89%; Cl-8.46%.

(q) 2-Ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 77% of theory.

M.p. 108°-109° C.

Calculated: C-69.68%; H-7.12%; N-7.07%. Found: C-70.00%; H-7.99%;N-7.31%.

(r)2-Hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 61% of theory.

M.p. 136°-138° C.

Calculated: C-70.22%; H-7.37%; N-6.82%. Found: C-70.40%; H-7.64%;N-6.60%.

(s)2-Isopropoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-isopropoxy-4-[N-{1-(2-piperidinophenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 67% of theory.

M.p. 115°-118° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.94%; H-7.96%;N-6.04%.

(t)2-Allyloxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-allyloxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 92% of theory.

M.p. 110°-112° C.

Calculated: C-71.97%; H-7.61%; N-6.22%. Found: C-71.90%; H-7.62%;N-6.21%.

(u)2-Benzyloxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl)-benzoicacid

Prepared from ethyl2-benzyloxy-5-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 95% of theory.

M.p. 161°-163° C.

Calculated: C-74.37%; N-7.25%; N-5.60%. Found: C-74.40%; N-7.44%;N-5.64%.

(v)(+)-2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]benzoate.

Yield: 81% of theory.

M.p. 122°-123° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.19%; H-7.77%;N-6.29%.

Specific rotation [α]_(D) ²⁰ =4.75° (c=1.03 in methanol).

(w)3-Methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from methyl3-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 64% of theory.

M.p. 188°-191° C.

Calculated: C-70.73%; H-7.60%; N-6.60%. Found: C-7.88%; H-7.56%;N-6.59%.

(x)3-Ethoxy-4-[N-{-1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoicacid

Prepared from ethyl3-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 79% theory.

M.p. 159°-165° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.32%; H-7.62%;N-6.24%.

(y)3-Ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl-}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl3-ethoxy-4-[N-{-1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 71% of theory.

M.p. 186°-188° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.70%; H-7.86%;N-6.26%.

(z)3-Ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl3-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 65% of theory.

M.p. 174°-176° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-72.00%; H-8.10%;N-5.91%.

(aa)2-Ethoxy-4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 41% of theory.

M.p. 127°-129° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-73.80%; H-7.09%;N-5.74%.

(ab)2-Ethoxy-4-[N(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 40% of theory.

M.p. 118°-121° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-73.71%; H-6.92%;N-5.76%.

(ac)2-Ethoxy-4-[N-{α-(4-methyl-phenyl)-2-piperidino-benzyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4[N-{α-(4-methyl-phenyl)-2-piperidino-benzyl}-aminocarbonylmethyl]-benzoate.

Yield: 94% of theory.

M.p. 148°-151° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-74.20%; H-7.15%;N-5.81%.

(ad)2-Methoxy-4-[N-{α-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from methyl2-methoxy-4-[N-{α-(4-chloro-phenyl)-2-piperidino-benzyl}-aminocarbonylmethyl]-benzoate.

Yield: 77% of theory.

m.p. 177°-180° C.

Calculated: C-68.21%; H-5.93%; N-5.68%; Cl-7.19%. Found: C-68.10%;H-5.78%; N-5.53%; Cl-7.43%.

(ae)2-Ethoxy-4-[N-(α-phenyl-2-pyrrolidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(α-phenyl-2-pyrrolidinobenzyl)-aminocarbonylmethyl]-benzoate.

Yield: 67% of theory.

M.p. 141°-143° C.

Calculated: C-73.34%; H-6.59%; N-6.11%. Found: C-73.33%; H-6.74%;N-6.02%.

(af)2-Methoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from methyl2-methoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 90% of theory.

M.p. 154°-156° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.70%; H-7.00%;N-5.95%.

(ag)2-Ethoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(2-hexamethyleneimino-α-phenyl-benzyl)-aminocarbonylmethyl]-benzoate

Yield: 75% of theory.

M.p. 139°-141° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-73.90%; H-7.14%;N-5.79%.

(ah)2-Hydroxy-4[N-(α-phenyl-2-piperidino-benzyl)-aminocarboxymethyl]-benzoicacid

Prepared from ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoateby hydrolysis with 4 equivalents of 1N sodium hydroxide inethanol/dioxane.

Yield: 35% of theory.

M.p. 222°-224° C.

Calculated: C-72.95%; H-6.35%; N-6.30%. Found: C-73.00%; H-6.64%;N-6.28%.

(ai)2-n-Propoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from n-propyl2-n-propoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 41% of theory.

M.p. 168°-170° C.

Calculated: C-74.05%; H-7.04%; N-5.76%. Found: C-74.20%; H-7.19%;N-5.57%.

(ak)2-Allyloxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-allyloxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 69% of theory.

M.p. 172°-173° C.

Calculated: C-74.35%; H-6.66%; N-5.78%. Found: C-74.11%; H-6.50%;N-5.74%.

(al)2-Benzyloxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-benzyloxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Yield: 72% of theory.

M.p. 214°-215° C.

Calculated: C-76.38%; H-6.41%; N-5.24%. Found: C-76.18%; H-6.39%;N-5.36%.

(am)(-)-2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl(-)-2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoate.

Yield: 89% of theory.

M.p. 90°-95° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.59%; H-6.81%;N-5.83%.

Specific rotation: [α]_(D) ²⁰ =-2.2° (c=1in methanol).

(an)3-Methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from methyl3-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 72% of theory.

M.p. 220°-221° C.

Calculated: C-73.34%; H-6.59%; N-6.11%. Found: C-73.36%; H-6.46%;N-5.85%.

(ao)3-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl3-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 70% of theory.

M.p. 199°-201° C.

Calculated: C-73.70%; H-6.83%; N-5.93%. Found: C-73.50%; H-6.74%;N-5.94%.

(ap)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}-aminocarbonylmethyl]-benzoicaid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-heptyl}-aminocarbonylmethyl]-benzoate.

Yield: 88% of theory.

M.p. 71°-73° C.

Calculated: C-72.47%; H-8.39%.; N-5.83%. Found: C-72.28%; H-8.56%;N-5.82%.

EXAMPLE 5 Sodium salt of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoicacid×1.5 H₂ O

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoateanalogous to Example 4. After purification by column chromatography theevaporation residue was dissolved in ethanol and mixed with 1 equivalentof 1N sodium hydroxide. By evaporation in vacuo and trituration withacetone, the crystalline sodium salt was obtained.

Yield: 76% of theory.

M.p. 242°-244° C.

Calculated: C-62.73%; H-7.01%; N-6.01%. Found; C-62.74%; H-7.17%;N-6.05%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 5:

(a) Sodium salt of2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid×0.5 H₂ O

Prepared from ethyl2-ethoxy-4-[N-{1-(4-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 72% of theory.

M.p. 255°-260° C.

Calculated: C-67.06%.; H-7.50%; N-5.79%. Found: C-66.94%; H-7.28%;N-5.50%.

(b) Sodium salt of2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid×2.5 H₂ O

Prepared from ethyl2-ethoxy-4-[N-{1-(6-methyl-2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 81% of theory.

M.p. 232°-240° C.

Calculated: C-62.39%; H-7.75%; N-5.39%. Found: C-62.22%; H-7.46%;N-5.61%.

(c) Sodium salt of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 87% of theory.

M.p. 250°-258° C.

Calculated: C-67.79%; H-7.22%; N-6.08. Found: C-67.60%; H-7.37%;N-6.04%.

(d) Sodium salt of2-ethoxy-4-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 89% of theory.

M.p. 233°-235° C.

Calculated: C-70.42%; H-6.32%; N-5.67%. Found: C-70.20%; H-6.41%;N-5.49%.

EXAMPLE 6 Ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

1 ml (10.4 mmols) of boron tribromide was added dropwise at -20° C.under anhydrous conditions to a stirred solution of 2 g (4 mmols) ofethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein 20 ml of 1,2-dichloroethane. The mixture was allowed to reach roomtemperature and was then stirred for 17 hours. It was then poured intoethanol, evaporated in vacuo, ice was added, and the resulting mixturewas taken up in a mixture of chloroform and water. The evaporationresidue was purified by column chromatography on silica gel(toluene/ethyl acetate=5/1).

Yield: 0.37 g (21% of theory).

M.p. 172°-173° C.

Calculated: C-73.70%; H-6.83%; N-5.91%. Found: C-73.95%; H-7.05%;N-6.12%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 6:

(a)2-Hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid.

Yield: 40% of theory.

M.p. 221°-223° C.

Calculated: C-72.95%; H-6.35%; N-6.30%. Found: C-72.68%; H-6.45%;N-6.49%.

(b) Ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-ethoxy-4[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 19% of theory.

M.P. 132°-134° C.

Calculated: C-71.21; H-7.81; N-6.39. Found: C-71.43%; H-7.91%; N-6.55%.

c)2-Hydroxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoicacid

Prepared from2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoicacid

Yield: 42% of theory.

M.p. 136°-137° C.

Calculated: C-70.22%; H-7.37%; N-6.82%. Found: C-70.19%; H-7.39%;N-6.99%.

EXAMPLE 7 Tert.butyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

A mixture of 1.9 g (9.6 mmols) of N,N'-dicyclohexyl-carbodiimide, 1.06ml (11.2 mmols) of absolute tert.butanol and 0.020 g (0.20 mmol) ofcopper(I) chloride was stirred for 60 hours at room temperature. Then,6.6 ml of methylene chloride were added, and the resulting solution wasadded dropwise to a solution of 0.44 g (1 mmol) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid in 15 ml of methylene chloride. After 60 hours' stirring at 20° C.,the precipitate which had formed was filtered off, washed with methylenechloride, and the methylene chloride solution was evaporated in vacuo.The evaporation residue was purified by column chromatography on silicagel (chloroform/ethyl acetate-9/1).

Yield: 0.30 g (60% of theory).

M.p. 74°-77° C. (from petroleum ether).

Calculated: C-72.84%; H-8.56; N-5.66%. Found: C-73.00%; H-8.65%;N-5.79%.

EXAMPLE 8 Ethyl2-benzyloxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

0.10 g (2.3 mmols) of sodium hydride (55% in oil) was added to asolution of 1.1 g (2.3 mmols) of ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein 10 ml of anhydrous dimethylformamide and the resulting mixture wasstirred for half an hour at room temperature. Then, a solution of 0.27ml (2.3 mmols) of benzyl bromide in 5 ml of anhydrous dimethylformamidewas added dropwise, and the resulting mixture was stirred for 5 hours atroom temperature. It was then evaporated in vacuo, the residue was takenup in a mixture of dilute sodium hydroxide and chloroform, and theorganic phase was dried, filtered and evaporated in vacuo. Theevaporation residue was recrystallized from acetonitrile.

Yield: 0.9 g (69.5% of theory).

M.p. 156°-157° C.

Calculated: C-76.84%; H-6.81%; N-4.98%. Found: C-76.94%; H-6.95%;N-4.87%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 8:

(a) Ethyl2-allyloxy-4[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate,using allyl bromide.

Yield: 46% of theory.

M.p. 117°-119° C.

Calculated: C-74.97%; H-7.08%; N-5.47%. Found: C-74.90%; H-7.14%;N-5.38%.

(b) Ethyl2-isopropoxy-4-[N-{-1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1butyl}-aminocarbonylmethyl]-benzoate,using 1.5 equivalents of isopropyl bromide at 150° C.

Yield: 56% of theory.

M.p. 98°-99° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.60%; H-8.60%;N-5.75%.

(c) Ethyl2-allyloxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate,using allyl bromide.

Yield: 72% of theory.

M.p. 105°-106° C.

Calculated: C-72.77%; H-8.00%; N-5.85%. Found: C-72.90%; H-7.90%;N-5.87%.

(d) Ethyl2-benzyloxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate,using benzyl bromide.

Yield: 80% of theory.

M.p. 135°-136° C.

Calculated: C-74.97%; H-7.63%; N-5.30%. Found: C-75.20%; H-7.78%;H-5.59%.

EXAMPLE 9 n-Propyl2-n-propoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from2-hydroxy-4-(N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid analogous to Example 8, using 2 equivalents of sodium hydride and 2equivalents of n-propyl bromide.

Yield: 45% of theory.

M.p. 118°-120° C.

Calculated: C-74.97%; H7.63%; N-5.30%. Found: C-75.20%; H-7.80%;N-5.41%.

The following compound was obtained by a procedure analogous to thatdescribed in Example 9:

(a) n-Propyl2-n-propoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from n-propyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

Yield: 39% of theory.

M.p. 89°-90° C.

Calculated: C-72.84%; H-8.56%; N-5.66%. Found: C-72.95%; H-8.77%;N-5.59%.

EXAMPLE 10 Ethyl2-ethoxy-4-[N-(2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

1.0 g (2.18 mmols) of ethyl2-ethoxy-4-[N-(5-chloro-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatewas hydrogenated in 20 ml of ethanol with 0.5 g of 10% ofpalladium-on-charcoal at 50° C. under 1 bar of hydrogen for 45 minutes.The reaction mixture was filtered through diatomaceous earths, thefiltrate was evaporated in vacuo, and the residue was purified by columnchromatography on silica gel (chloroform/methanol-10/1).

Yield: 0.71 g (77% of theory).

M.p. 83°-84° C. (from petroleum ether).

Calculated: C-70.73%; H-7.60%; N-6.60%. Found: C-70/89%; H-7.66%;N-6.76%.

The following compound was obtained by a procedure analogous to thatdescribed in Example 10:

(a) Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-ethoxy-4-[N-{1-(5-chloro-2-piperidino-phenyl)-1-propyl}-aminocarbonylmethyl]-benzoate.

Yield: 74% of theory.

M.p. 115°-117° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.47%; H-8.11%;N-6.25%.

EXAMPLE 112-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid (form A)

(a)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1yl}-aminocarbonylmethyl]-benzoicacid.

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate.

Yield: 85% of theory.

M.p. 110°-113° C.

Calculated: C-71.97%; H-7.61%; N-6.22%. Found: C-71.92%; H-7.80%;N-5.98%.

(b) 0.21 g (0.39 mmol) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoicacid were hydrogenated in 10 ml of absolute ethanol with 0.10 g of 10%palladium-on-charcoal at 50° C. and a pressure of 1 bar of hydrogen for7 hours. The reaction mixture was then filtered through diatomaceousearth, the reaction filtrate was evaporated in vacuo, and the residuewas purified by column chromatography on silica gel(chloroform/methanol=10/1).

Yield: 0.10 g (47% of theory).

M.p. 90°-92° C. (recrystallized from acetone/petroleum ether).

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.50%; H-8.12%;N-6.45%.

2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid, is also obtained in other solid forms when it is crystallized fromother solvents or mixtures of solvents. Form (B), which has a meltingpoint of 140° to 142° c., is obtained by crystallization from anethanol/water mixture. The foamy form (C), which has a melting pointrange from 75° to 85° C., is obtained from the 1:1 methanol adduct(melting point: 85° to 90° C.), which occurs upon crystallization frommethanol, by heating at 60° C. in vacuo (5 Torr) over phosphoruspentoxide, whereby the methanol is removed.

In the dissolved state these forms are identical, as is evident from thecorresponding solution spectra, for instance the IR-spectra in methylenechloride shown in FIGS. 1, 2 and 3 of the attached drawings. However, inthe solid state, the three forms differ in their melting characteristicsand their solid spectra, for instance as shown by the correspondingIR-KBr-spectra in FIGS. 4, 5 and 6 of the attached drawings.

In order to measure infra-red absorption, forms (A), (B) and (C) weredissolved in methylene chloride (40 mg of substance per ml of methylenechloride), or intimately triturated with potassium bromide and thencompressed hydraulically to form a tablet (approx. 1 mg of substance/300mg of KBr).

In the case of the solutions, the IR-spectra were measured with anIR-spectrometer (Perkin Elmer Type 299) in a cell of sodium chloride(layer thickness 0.2 mm) by comparison with a pure methylene chloridesolution and, in the case of the potassium bromide tablets, with anIR-spectrometer (Perkin Elmer Type 298) by comparison with air.

The three solid forms can be converted into one another by suitablerecrystallization and drying. Thus, the low-melting-point form (A) isobtained by recrystallizing the high-melting-point form (B) fromacetone/petroleum ether and the high-melting-point form (B) is obtainedby recrystallizing the low-melting-point form (A) from ethanol/water. Byrecrystallizing the high-melting-point form (B) from methanol, a 1:1adduct with methanol is obtained, and from this the foamy form (C) isobtained by removing the methanol.

Irrespective of the particular process which is used to synthesize2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid, therefore, the high-melting-point or low-melting-point or foamyform can be obtained, as desired, by a suitable choice of solvent ormixture of solvents during crystallization and by suitable drying. Thisis important in the practical use of the solid forms, whether or notthey are accompanied by galenic excipients in pharmaceuticalcompositions, particularly for lowering blood sugar in the treatment ofType II diabetes; this is because different solid forms may havedifferent shelf lives and/or different absorption characteristics invivo and may thus give a different pattern of biological activity.

2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid may be obtained by the methods described hereinabove, butpreferably by reacting 3-methyl-1-(2-piperidino-phenyl)-1-butylaminewith a compound of the formula ##STR17## wherein W is carboxyl orcarboxyl protected by a protective group or with a relative derivativethereof, optionally prepared in the reaction mixture, followed, ifnecessary, by removal of the protective group, and the solid forms (B)and (C) are obtained by suitable subsequent crystallization, suitablefinal recrystallization and/or drying.

Examples of reactive derivatives of a compound of the formula XI includethe esters such as the methyl, ethyl and benzyl esters thereof, thethioesters such as the methylthio and ethylthioesters, the halides suchas the acid chloride, the anhydrides and imidazolides thereof.

The reaction is advantageously carried out in a solvent such asmethylene chloride, chloroform, carbon tetrachloride, ether,tetrahydrofuran, dioxane, benzene, toluene, acetonitrile ordimethylformamide, optionally in the presence of an acid-activatingagent or a dehydrating agent, for instance in the presence of ethylchloroformate, thionyl chloride, phosphorus trichloride, phosphoruspentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, or in the presence of an aminogroup activating agent, such as phosphorus trichloride, and optionallyin the presence of an inorganic base such as sodium carbonate or atertiary organic base such as triethylamine or pyridine, which maysimultaneously serve as solvent, at temperatures between -25° and 250°C., but preferably at temperatures between -10° C. and the boiling pointof the solvent which is used. The reaction may also be carried outwithout a solvent, and any water formed during the reaction may beremoved by azeotropic distillation, for instance by heating withtoluene, using a water trap, or by adding a drying agent such asmagnesium sulfate or a molecular sieve.

The subsequent removal of the protective group is preferably carried outby hydrolysis, either in the presence of an acid such as hydrochloric,sulfuric, phosphoric or trichloroacetic acid, or in the presence of abase such as sodium hydroxide or potassium hydroxide, in a suitablesolvent such as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxane at temperatures between -10° and 120°C., for instance at temperatures between room temperature and theboiling point of the reaction mixture.

A tert.butyl protective group may also be removed thermally, optionallyin an inert solvent such as methylene chloride, chloroform, benzene,toluene, tetrahydrofuran or dioxane, and preferably in the presence of acatalytic quantity of an acid such as p-toluenesulfonic, sulfuric,phosphoric or polyphosphoric acid.

Moreover, a benzyl protective group may also be removed by hydrogenationin the presence of a hydrogenation catalyst such aspalladium-on-charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide.

The subsequent crystallization is carried out in situ from the reactionmixture containing ethanol/water or, as in final recrystallization, bydissolving the reaction product in a mixture of ethanol and water,optionally while heating, and cooling, optionally accompanied bytrituration and/or seeding (form B), or by dissolving the reactionproduct in acetone and adding petroleum ether (form A), or by dissolvingthe reaction product, optionally while heating in methanol, subsequentcooling of the solution accompanied by trituration and/or seeding, andheating the isolated solid methanol adducts, preferably in vacuo, in thepresence of a drying agent such as phosphorus pentoxide (form C).

Like the other compounds of the formula I, solid forms (A), (B) and (C)of2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid may also be converted into their salts, particularly theirnon-toxic, pharmacologically acceptable table salts with inorganic ororganic acids or bases. Suitable acids for this purpose are, forexample, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic,citric, trataric, succinic, maleic or fumaric acid, and suitable basesare sodium hydroxide, potassium hydroxide, calcium hydroxide,cyclohexylamine, ethanolamine, diethanolamine, triethanolamine,ethylenediamine or lysine.

The melting points in Examples 12-16 were determined n anElectrothermal® melting point apparatus with visual observation of thesample of product in a capillary tube fused at one end.

EXAMPLE 12 Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoate

3 g (11.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g(14.3 mmols) of triphenylphosphine, 3.3 ml (23. 8 mmols) oftriethylamine and 1.15 ml (11.9 mmols) of carbon tetrachloride wereadded successively to a solution of 2.9 g (11.9 mmols) of3-methyl-1-(2-piperidino-phenyl)-1-butylamine in 29 ml of acetonitrile.The mixture was then stirred for 15 hours at room temperature, thesolvent was removed in vacuo, and the residue was taken up in a mixtureof ethyl acetate and water. The organic phase was dried over sodiumsulfate, filtered and concentrated by evaporation in vacuo. Theevaporation residue was purified by column chromatography on silica gel(toluene/acetone=10/1).

Yield: 4.9 g (85% of theory).

M.p. 143°-145° C. (petroleum ether).

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.37%; H-8.45%;N-6.07%.

EXAMPLE 13 High-melting point form (B) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid

A mixture of 4.7 g (9.7 mmols) of ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoateand 14.7 ml of 1N sodium hydroxide was stirred in 47 ml of ethanol for 2hours at 60° C., then neutralized with 14.7 ml of 1N hydrochloric acidand cooled to 0° C. The mixture was filtered to remove the precipitatedcolorless crystals, and the crystals were washed with ice water and witha little ice cold ethanol and then dried at 100° C./1 Torr.

Yield: 3.9 g (88% of theory).

M.p. 140°-142° c.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.90%; H-8.08%;N-6.34%.

Upon further recrystallization from ethanol/water (2/1) the meltingpoint remained constant.

EXAMPLE 14 Low-melting-point form (A) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid

1.0 g of the high-melting-point form (B) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid was dissolved at room temperature in 5 ml of acetone, and 5 ml ofpetroleum ether (m.p. 60°-70° C.) were added. Upon trituration,crystallization gradually set in. The same quantity of petroleum etherwas added again, and after crystallization had ended, the mixture wasfiltered. The crystals were washed with petroleum ether, and the almostcolorless crystals were dried for 2 hours at 60° C./0.1 Torr.

Yield: 0.7 g.

M.p. 95°-98° C. (clear beginning at 135° C.).

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.80%; H-8.04%;N-5.92%.

The IR-spectra for this form (see FIGS. 1 and 4) are identical to theIR-spectra for the form (A), melting point 90°-92° C., described inExample 11(b) above.

EXAMPLE 15 High-melting-point form (B) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid

1.0 g of the low-melting-point form (A) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid was dissolved in 10 ml of ethanol/water (2/1) while heating over asteam bath. The solution was then cooled to 0° C., whereuponcrystallization began. The mixture was filtered, and the residue waswashed with a little ice-cold ethanol and dried at 100° C./1 Torr.

Yield: 0.8 g.

M.p. 140°-142° C.

EXAMPLE 16

Foamy form (C) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid

1.5 g of the high-melting-point form (B) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl-]benzoicacid was dissolved in 5 ml of methanol while heating. The solution wasthen cooled to 0° C. with trituration. The crystals precipitated therebywere separated by filtration, washed with a little cold methanol, anddried for 2 hours at 60° C./1 Torr.

Yield of adduct (with 1×CH₃ OH): 1.2 g.

M.p. 85°-90° C.

Calculated: (×1 CH₃ OH): C-69.39%; H-8.32%; N-5.78%. Found: C-69.20%;H-8.20%; N-5.92%.

The adduct was converted into the methanol-free foamy form (C) byheating for 24 hours at 60° C/5 Torr over phosphorus pentoxide.

Melting range: 75°-85° C.

Calculated: C-71.65%; H-8.02%; N-6.19%. Found: C-71.82%; H-8.06%;N-6.03%.

EXAMPLE 17 Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoate

Prepared from ethyl2ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate,melting point 125°-126° C., which in turn was prepared from(2-piperidino-phenyl)-isobutyl-ketimine and3-ethoxy-4-ethoxy-carbonyl-phenyl-acetic acid analogous to Example 1.

Yield: 51% of theory.

M.p. 139°-141° C.

Calculated: C-72.47%; H-8.39%; N-5.83%. Found: C-72.30%; H-8.20%;N-5.87%.

EXAMPLE 182-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzylalcohol

A solution of 1.8 g (3.6 mmols) of ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein 20 ml of absolute tetrahydrofuran was added dropwise at -5° C. to amixture of 0.28 g (7.4 mmols) of lithium aluminum hydride and 50 ml ofabsolute tetrahydrofuran, and the resulting mixture was stirred for 3hours at 0° C. It was then diluted with absolute ether, and 4N sodiumhydroxide was added. The mixture was filtered through diatomaceousearth, the filtrate was evaporated in vacuo, and the residue waspurified by column chromatography on silica gel (toluene/ethylacetate=2/1).

Yield: 0.51 g (31% of theory).

M.p. 133°-135° C.

Calculated: C-75.95%; H-7.47%; N-6.11%. Found: C-75.97%; H-7.55%;N-5.95%.

The following compound was obtained by a procedure analogous to thatdescribed in Example 18:

(a)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl-}aminocarbonylmethyl]-benzylalcohol

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoateby reduction with lithium borohydride in boiling tetrahydrofuran in thepresence of 10% of trimethyl borate.

Yield: 68% of theory.

M.p. 112°-115° C.

Calculated: C-73.55%; H-8.55%; N-6.60%. Found: C-73.60%; H-8.38%;N-6.69%.

EXAMPLE 192-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzaldehyde

A solution of 0.4 g (0.87 mmol) of2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzylalcohol was added dropwise at room temperature to a stirred solution of0.28 g (1.3 mmols) of pyridinium chlorochromate in 5 ml of chloroform.The reaction mixture was stirred overnight at room temperature,evaporated in vacuo, the residue was mixed with ether, the etheralmixture was filtered, the filtrate was evaporated in vacuo, and theresidue was purified by column chromatography on silica gel(toluene/ethyl acetate=2/1).

Yield: 0.16 g (40% of theory).

M.p. 154°-156° C.

Calculated: C-76.29%; H-7.06%; N-6.14%. Found: C-76.30%; H-7.15%;N-6.10%.

The following compound was obtained by a procedure analogous to thatdescribed in Example 19:

(a)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzaldehyde

Prepared from2-ethoxy-4[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzylalcohol.

Yield: 47% of theory.

M.p. 109°-111° C.

Calculated: C-73.90%; H-8.11%; N-6.63%. Found: C-74.22%; H-8.14%;N-6.73%.

EXAMPLE 202-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde

0.67 g (5.6 mmols) of sodium carbonate was heated together with 6 ml ofethylene glycol on an oil bath at 170° C. and then, while rapidlystirring, 0.70 g (1.1 mmols) of N¹-[2-ethoxy-4-{N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl}-benzoyl]-N²-tosyl-hydrazine were added thereto within a minute; a violent evolutionof gas was observed. Then, the mixture was heated for 2 minutes more at170° C. and then poured immediately over ice. The aqueous mixture wasextracted with ether, and the extract was dried, filtered and evaporatedin vacuo. The evaporation residue was purified by column chromatographyon silica gel (toluene/ethyl acetate=2/1).

Yield: 0.25 g (50% of theory).

M.p. 153°-156° C.

Calculated: C-76.29%; H-7.06%; N-6.14%. Found: C-76.42%; H-7.33%;N-6.28%.

The following compound was obtained by a procedure analogous to thatdescribed in Example 20:

(a)2-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl{-aminocarbonylmethyl]-benzoate

Prepared from N¹-[2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoyl]-N²-tosyl-hydrazine.

Yield: 51% of theory.

M.p. 108°-111° C.

Calculated: C-73.90%/ H-8.11%; N-6.63%. Found: C-73.79%; H-8.29%;N-6.75%.

EXAMPLE 21 Benzyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

0.35 g (0.8 mmol) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid was refluxed together with 0.15 g (0.9 mmol) ofN,N'-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2hours. Then, 1.03 ml (10 mmols) of benzyl alcohol were added, and themixture was refluxed for 3.5 hours. The reaction mixture was thenevaporated in vacuo, and the residue was purified by columnchromatography on silica gel (chloroform/acetone=9/1).

Yield: 0.10 g (23.6% of theory).

M.p.<20° C.

Calculated: Mol peak m/e=528. Found: Mol peak m/e=528.

EXAMPLE 22 Ethyl(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoateand Ethyl(-)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

28 mg of ethyl(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoatewere added in 0.02 mg-portions to a chiral phase HPLC column made by theBaker Co., in which (R)-N-3,5-dinitrobenzoyl-phenylglycine wascovalently bonded to aminopropyl-silica gel (5 μm particle size,spherical, pore size 60 Å; 4.6 mm internal diameter, 25 cm in length).

Flow agent: hexane/ethanol=100/5.

Flow rage: 0.75 ml/minute.

Temperature: 22° C.

The fractions eluted at 31.2 minutes and at 32.9 minutes (UV detectionat 254 nm) were separately recovered, collected and evaporated in vacuo.

The following was obtained from the 31.2-minute eluate: 7.5 mg of ethyl(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

M.p. 117°-119° C.

Specific rotation: [α]_(D) ²⁰ =+7.0° (c=1.03 in methanol).

The following was obtained from the 32.9-minute eluate: 9.4 mg of ethyl(-)-2-ethoxy-4-N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate.

m.p 115°-117° C.

Specific rotation: [α]_(D) ²⁰ =-6.9° (c=1.02 methanol).

Analogous to Example 22,

(a) Ethyl(+)-2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

was separated into its (+) enantiomer and its (-) enantiomer.

EXAMPLE 23 Ethyl2-acetoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate

A mixture of 0.02 g (0.46 mmol) of ethyl2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate,0.34 ml (3.65 mmols) of acetic acid anhydride and 20 μl of concentratedsulfuric acid was stirred for 40 hours at 70° C. The mixture was thenevaporated in vacuo, the residue was taken up in a mixture of water andether, and neutralized with sodium carbonate. The etheral phase wasseparated, and the aqueous phase was extracted twice with ethyl acetate.The combined organic extracts were dried, filtered and evaporated invacuo. The evaporation residue was purified by column chromatography onsilica gel (toluene/acetone=10/1).

Yield: 50% of theory.

M.p.133°-135° C. (from petroleum ether).

Calculated: C-69.98%; H-7.55%; N-5.83%. Found: C-69.75%; H-7.32%;N-5.74%.

The following compounds were obtained by a procedure analogous to thatdescribed in Example 23:

(a)2-Acetoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl)-(aminocarbonylmethyl]-benzoicacid

Prepared from2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid.

Yield: 12% of theory.

M.p. 125°-127° C.

Calculated: Mol peak m/e=452. Found: Mol peak m/e=452.

(b) Ethyl2-acetoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared from ethyl2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Yield: 23.5% of theory.

M.p. 163°-166° C.

Calculated: C-72.35%; H-6.66%; N-5.44%. Found: C-72.41%; H-6.75%;N-5.31%.

(c)2-Acetoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared from2-hydroxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid.

Yield: 17% of theory.

M.p. 126°-128° C.

Calculated: C-71.58%; H-6.21%; N-5.76%. Found: C-71.77%; H-6.57%;N-5.81%.

EXAMPLE 242-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-toluene

A mixture of 0.54 g (1.2 mmols) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzylchloride (melting point 114°-115° C., prepared from2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl-benzylalcohol and thionyl chloride in chloroform) and 10 ml of absolutedioxane was hydrogenated for 3 hours at 20° C. and a pressure of 5 barhydrogen. The reaction mixture was then evaporated in vacuo, and theresidue was taken up in a mixture of ethyl acetate and aqueous sodiumcarbonate. The organic phase was dried, filtered and evaporated invacuo. The evaporation residue was purified by column chromatography onsilica gel (chloroform/acetone=19/1).

Yield: 0.23 g (47% of theory).

M.p. 107°-108° C.

Calculated: C-76.43%; H-8.88%; N-6.86%. Found: C-76.40%; H-8.88%;N-6.90%.

EXAMPLE 252-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

100 mg (0.20 mmol) of tert.butyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonyl]-benzoatewere refluxed in 5 ml of benzene together with a few crystals ofp-toluene-sulfonic acid hydrate for half a day. The desired product wasobtained, as confirmed by thin-layer chromatography, by the R_(f) -valueand mass spectrum.

M.p. 87°-89° C.

Calculated: m/e=438. Found: m/e=438.

EXAMPLE 362-Ethoxy-4-[N-{1(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

0.25 g (0.47 mmol) of benzyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoatewas hydrogenated in 10 ml of ethanol with 0.12 g of 10%palladium-on-charcoal at 50° C. and a pressure of 5 bar of hydrogen.After 5 hours the catalyst was filtered off through diatomaceous earth,and the filtrate was evaporated in vacuo. The evaporation residue wascrystallized from petroleum ether/ethanol.

Yield: 0.14 g (70% of theory).

M.p. 87°-90° C.

Calculated: C-71.21%; H-7.81%; N-6.39%. Found: C-71.46%; H-7.95%;N-6.51%.

EXAMPLE 27 Ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-n-hexyl}-aminocarbonylmethyl]-benzoate

Prepared from 1-(2-piperidino-phenyl)-1-n-hexylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogous to Example 1.

Yield: 43% of theory.

M.p. 101°-105° C.

Calculated: C-72.84%; H-8.56%; N-5.66%. Found: C-72.72%; H-8.52%;N-5.63%.

EXAMPLE 282-Ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-n-hexyl}-aminocarbonylmethyl]-benzoicacid

Prepared from ethyl2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-n-hexyl}-aminocarbonylmethyl]-benzoateanalogous to Example 4.

Yield: 77% of theory.

M.p. 117°-120° C.

Calculated: C-72.07%; H-8.21%; N-6.00%. Found: C-72.00%; H-8.06%;N-5.90%.

EXAMPLE 29[2-Ethoxy-4[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-acetonitrile

To a solution of2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzylchloride (2 g; 4.5 mmol) [prepared from2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzylalcohol with thionyl chloride in chloroform], is added sodium cyanide(0.255 g, 5.2 mmol), dissolved in water (2.2 ml), and the phase transfercatalyst benzyl tributylammonium chloride (0.069 g, 0.22 mmol) and themixture is stirred for 5 days at ambient temperature. Then, furtherphase transfer catalyst (0.069 g) is added, together with a few smallgrains of potassium iodide and sodium cyanide (0.2 g) in water (1 ml)and the mixture is stirred for a further 24 hours; then the same amountsof these three components are added again and the mixture is stirred fora further 12 hours. Methylene chloride (40 ml) is added and the mixtureis extracted twice with water. The methylene chloride phase is driedover sodium sulphate/potassium carbonate, filtered and concentrated byevaporation in vacuo. The evaporation residue is purified by columnchromatography on silica gel (toluene/ethyl acetate=5/1).

Yield: 1.53 g,

Melting point: 116°-118° C. (methylene chloride/ether)

Calculated: C 74.79; H 8.14; N 9.69. Found: C 74.86; H 8.19; N 9.42.

EXAMPLE 30[2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-acetonitrile

A solution of2-ethoxy-4[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzylchloride (2.6 g, 5.45 mmol) in dimethylsulphoxide (10 ml) is addeddropwise at 50°-60° C. to sodium cyanide (0.32 g, 6.5 mmol) indimethylsulphoxide (40 ml). The mixture is then stirred for 5 hours at60° C., added to water and extracted with chloroform. The extract isconcentrated by evaporation in vacuo. The residue is purified by columnchromatography on silica gel (toluene/ethyl acetate=5/1).

Yield: 1.2 g,

Melting point: 145°-148° C.

Calculated: C 77.05; H 7.11; N 8.99. Found: C 76.92; H 7.05; N 8.78.

EXAMPLE 31 Ethyl[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-acetate

Dry hydrogen chloride is introduced for 3 hours into a stirred andboiling solution of[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-acetonitrile(1.3 g, 3 mmol) in absolute ethanol (30 ml). The mixture is thenevaporated from in vacuo, water (25 ml) is added to the evaporationresidue and this is stirred for 15 minutes at 50° C. The mixture isadjusted to a pH of 7 by the addition of solid sodium hydrogen carbonateand is extracted three times with ethyl acetate. The combined organicextracts are shaken once with water, then dried over sodiumsulphate/potassium carbonate, filtered and concentrated by evaporationin vacuo. The evaporation residue is purified by column chromatographyon silica gel (chloroform/ethyl acetate=9/1).

Yield: 1.0 g,

Melting point: 91°-93° C. (petroleum ether)

Calculated: C 72.47; H 8.39; N 5.83. Found; C 72.73; H 8.68; N 5.71.

EXAMPLE 32 Methyl[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)amino-carbonylmethyl]-phenyl]-acetate

Dry hydrogen chloride is introduced for 4 hours into a stirred andrefluxed solution of[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-acetonitrile(1.2 g, 2.57 mmol) in methanol (20 ml). The mixture is then concentratedby evaporation, added to water and extracted with chloroform. Theextract is dried and filtered and concentrated by evaporation in vacuo.The evaporation residue is purified by column chromatography on silicagel (toluene/ethyl acetate=4/1).

Yield: 340 mg,

Melting point: 136°-138° C. (acetonitrile/water)

Calculated: molecular peak m/e=500 Found: molecular peak m/e=500

EXAMPLE 33[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl-aminocarbonylmethyl]-phenyl]-aceticacid

A 1N sodium hydroxide solution (2.8 ml) is added to ethyl[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl-aminocarbonylmethyl]-phenyl]-acetate(0.67 g, 1.4 mmol) in ethanol (10 ml) and stirred for 4 hours at ambienttemperature. Then the mixture is evaporated down in vacuo at 50° C.Water and a few drops of methanol are added to the evaporation residuewhich is then adjusted to pH 6 with 1N acetic acid. It is cooled in ice,whereupon a precipitate is formed. This is filtered off andrecrystallised from ethanol/

Yield: 0.47 g,

Melting point: 158°-159° C. C 71.65; H 8.02; N 6.19. Found: C 71.35; H3.80; N 6.21.

EXAMPLE 34[2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-aceticacid

Prepared analogously to Example 5 alkaline saponification of methyl[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]acetate.

Melting point: 146°-148° C.

Calculated C 74.05; H 7.04; N 7.76. Found: C 73.70; H 7.00; N 5.85.

EXAMPLE 35 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl[-cinnamate

A solution of ethyl diethyl-phosphono-acetate (1.68 g, 7.5 mmol) inabsolute dioxan (3 ml) is slowly added dropwise, with vigorous stirring,to a suspension of 55% sodium hydride (in oil) (0.327 g, 7.5 mmol) inabsolute dioxan (4 ml). After the reaction has died down the mixture isheated to 80° C. for a further 45 minutes. It is then cooled to ambienttemperature, a solution of2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde(2.11 g, 5 mmol) [prepared from the corresponding benzyl alcohol byoxidation with pyridinium chlorochromate in chloroform] in absolutedioxan (4 ml) is added dropwise thereto and the mixture is heated for 2hours at 50° C. The reaction mixture is poured onto ice/water andextracted with chloroform. The organic extract is dried and filtered andevaporated down in vacuo. The evaporation residue is purified by columnchromatography on silica gel (chloroform/ethyl acetate=19/1).

Yield: 1.64 g,

Melting point: 130°-131° C. (ether)

Calculated: C 73.14; H 8.18; N 5.69. Found: C 73.36; H 8.34; N 5.75.

EXAMPLE 362-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamicacid nitrile

Prepared analogously to Example 7 from2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehydewith diethylphosphonoacetonitrile.

Melting point: 125°-128° C. (petroleum ether)

Calculated: C 75.47; H 7.92; N 9.43. Found: C 75.40; H 7.95; N 9.24.

EXAMPLE 37 Ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-amino-carbonylmethyl]-cinnamate

Under a nitrogen atmosphere, 50% sodium hydride (0.19 g, 8 mmol) isadded to a stirred solution of ethyl diethylphosphono-acetate (1.8 g, 8mmol) in absolute 1,2-dimethoxy-ethane (10 ml). Then a solution of2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde(2 g, 4.4 mmol) in absolute 1,2-dimethoxy-ethane (15 ml) is added andthe mixture is stirred for 30 minutes at ambient temperature. It isconcentrated by evaporation in vacuo and the evaporation residue isdistributed between water and chloroform. The chloroform extract isdried and filtered and concentrated by evaporation in vacuo. Theevaporation residue is purified by column chromatography on silica gel(toluene/ethyl acetate=5/1). Yield: 0.37 g.

Melting point: 111°-113° C. (cyclohexane)

Calculated: C 75.26; H 7.27; N 5.32. Found: C 75.14; H 7.32; N 5.25.

EXAMPLE 382-Ethoxy-4[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamicacid

A solution of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-cinnamate(0.49 g, 1 mmol) in ethanol (10 ml) is stirred together with 1N sodiumhydroxide solution (2 ml) for 3 days at ambient temperature. The mixtureis then concentrated by evaporation in vacuo, water and a few drops ofmethanol are added to the evaporation residue and this is then adjustedto pH 6 with 1N acetic acid. The precipitate is filtered off, dried andrecrystallized from ethyl acetate.

Yield: 0.37 g,

Melting point: 175°-177° C. (decomp.)

Calculated: C 72.39; H 7.81; N 6.03. Found: C 72.50; H 7.88; N 6.06.

EXAMPLE 392-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]cinnamicacid

Ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate(330 mg, 0.62 mmol) is dissolved in ethanol (10 ml) and, after theaddition of 4N sodium hydroxide solution (4 mo), stirred for 3 hours at50° C. Then the mixture is neutralized with 4N hydrochloric acid (4 ml),diluted with water and filtered off from the precipitate. It is thenrecrystallized from aqueous ethanol.

Yield: 210 mg,

Melting point: 181° C.

Calculated: C 74.67; H 6.87; N 5.62. Found: C 74.72; H 6.76; N 5.42.

EXAMPLE 40 Ethyl3-[2-ethoxy-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionate

A solution of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate(0.54 g, 1.1 mmol) in ethanol (15 ml ) is hydrogenated for 1 hour atambient temperature and under 3 bars of hydrogen on 10%palladium/charcoal (0.1 g). The mixture is filtered, concentrated byevaporation in vacuo and the evaporation residue is crystallized frompetroleum ether.

Yield: 0.30 g,

Melting point: 71°-73° C.

Calculated: C 72.84; H 8.56; N 5.66. Found: C 73.19; H 8.54; N 5.70.

EXAMPLE 41 Ethyl3-[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionate

Prepared analogously to Example 12 by catalytic hydrogenation of ethyl2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamateand subsequent purification by column chromatography on silica gel(cyclohexane/ethyl acetate/methanol=6/1/0.5).

Melting point: 130° C. (ethanol/water)

Calculated: C 74.97; H 7.63; N 5.30. Found: C 74.65; H 7.61; N 5.15.

EXAMPLE 423-[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionicacid

Prepared analogously to Example 12 by specific hydrogenation of2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamicacid.

Melting point: 112°-114° C.

Calculated: C 72.07; H 8.21; N 6.00. Found: C 72.30; H 8.42; N 6.19.

EXAMPLE 433-[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionitrile

Prepared analogously to Example 12 by catalytic hydrogenation of2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid nitrile.

Melting point: 102°-103° C. (petroleum ether)

Calculated: molecular peak m/e=447 Found: molecular peak m/e=447

EXAMPLE 443-[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionicacid

Prepared analogously to Example 5 by alkaline saponification of ethyl3-[-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionateand subsequent purification by column chromatography(chloroform/methanol=9/1).

Melting point: 112°-115° C. (petroleum ether)

Calculated: C 72.07; H 8.21; N 6.00. Found: C 72.40; H 8.21; N 6.03.

EXAMPLE 453-[2-Ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-phenyl]-propionicacid

Prepared analogously to Example 5 by alkaline saponification of ethyl3-[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-propionate.

Melting point: 74° C.

Calculated: C 74.37; H 7.25; N 5.60. Found: C 74.29; H 7.31; N 5.27.

EXAMPLE 463-[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionitrile

At ambient temperature, p-toluenesulphonic acid chloride (45.8 mg, 0.24mmol) is added to a mixture of3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionicacid amide, (56 mg, 0.12 mmol) melting point 153°-155° C. [prepared fromthe corresponding propionic acid by reacting with carbonyldiimidazoleand then with ammonia in tetrahydrofuran] and absolute pyridine (0.44ml). The mixture is stirred for 45 minutes at 20° C. and for 2 hours at50° to 60° C. After cooling, water is added, the mixture is madealkaline with concentrated ammonia and extracted three times withchloroform. The combined chloroform extracts are washed with water,dried over sodium sulphate, filtered and concentrated by evaporation invacuo. The evaporation residue is purified by column chromatography onsilica gel (chloroform/ethyl acetate=9/1).

Yield: 11 mg,

Calculated: molecular peak m/e=447 Found: molecular peak m/e=447

EXAMPLE 47 Ethyl2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

To a solution of α-cyclohexylmethyl-2-piperidino-benzylamine (1.13 g,3.96 mmol) in acetonitrile (11 ml) are added, successively,3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid (1 g, 3.96 mmol), oftriphenylphosphine (1.25 g, 4.76 mmol), triethylamine (1.11 ml, 7.92mmol) and carbon tetrachloride (0.38 ml, 3.96 mmol) and the mixture isstirred for 15 hours at ambient temperature. It is then concentrated byevaporation in vacuo and partitioned between ethyl acetate and water.The organic extract is dried and filtered and concentrated byevaporation in vacuo. The evaporation residue is purified by columnchromatography on silica gel (toluene/acetone=10/1).

Yield: 1.4 g,

Melting point: 95°-97° C. (petroleum ether/cyclohexane=1/1)

Calculated: C 73.81; H 8.52; N 5.38. Found: C 73.98; H 8.49; N 5.61.

EXAMPLE 48 Ethyl2-ethoxy-4-[N-(α-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 fromα-benzyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 102°-105° C. (petroleum ether)

Calculated: C 74.68; H 7.44; N 5.44. Found: C 74.73; H 7.68; N 5.39.

EXAMPLE 492-Ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Ethyl2-ethoxy-4-[N-(α-cyclohexyl-methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(1.15 g, 2.21 mmol) in ethanol (12 ml) are stirred together with 1Nsodium hydroxide solution (3.3 ml) for 2 hours at 50° C. Then 1Nhydrochloric acid (3.3 ml) is added and the mixture is cooled in ice.The precipitate formed is filtered off, washed with a little ice coldethanol and dried in vacuo at 100° C.

Yield: 0.9 g,

Melting point: 153°-156° C.

Calculated: C 73.14; H 8.18; N 5.69. Found: C 73.30; H 8.17; N 5.66.

EXAMPLE 502-Ethoxy-4-[N-(α-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-benzyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 100°-105° C.

Calculated: C 74.05; H 7.04; N 5.76. Found: C 73.77; H 7.10; N 5.50.

EXAMPLE 51 Ethyl2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

To a mixture of (2-piperidino-phenyl)-glycine-ethylester-dihydrochloride (2 g, 5.96 mmol) in acetonitrile (12 ml) are addedsuccessively 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid, (1.52 g, 5.96mmol) triphenylphosphine (1.77 g, 6.75 mmol), triethylamine (2.45 ml,17.9 mmol) and carbon tetrachloride (0.57 ml, 5.96 mmol) and the mixturesi stirred overnight at ambient temperature. It is then concentrated byevaporation in vacuo and partitioned between chloroform and water. Theorganic extract is dried and filtered and concentrated by evaporation invacuo. The evaporation residue is purified by column chromatography onsilica gel (toluene/acetone=4/1).

Yield: 1.2 g,

Melting point: 100°-103° C. (ether)

Calculated: C 67.72; H 7.31; N 5.64. Found: C 67.87; H 7.46; N 5.61.

EXAMPLE 52 Benzyl2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 23 from(2-piperidino-phenyl)-glycine-ethyl ester-dihydrochloride and3-ethoxy-4-benzyloxycarbonyl-phenyl acetic acid.

Melting point: 90°-93° C.

Calculated: molecular peak m/e=558 Found: molecular peak m/e=558

EXAMPLE 53 Benzyl2-ethoxy-4-[N-(α-methoxycarbonyl-2piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 23 from(2-piperidino-phenyl)-glycine-methyl ester-dihydrochloride and3-ethoxy-4-benzyloxycarbonyl-phenyl acetic acid.

Melting point: 100°-102° C. (ether)

Calculated: C 70.57; H 6.66; N 5.14. Found: C 70.46; H 6.67; N 5.14.

EXAMPLE 54 Benzyl2-ethoxy-4-[N-(α-propoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 23 from(2-piperidino-phenyl)-glycine-n-propylester-dihydrochloride and3-ethoxy-4-benzyloxycarbonyl-phenylacetic acid.

Melting point: 100°-102° C. (petroleum ether)

Calculated: C 71.31; H 7.04; N 4.89. Found: C 71.62; H 7.01; N 4.97.

EXAMPLE 55 Benzyl2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 23 from(2-piperidino-phenyl)-glycine-isopropylester-dihydrochloride and3-ethoxy-4-benzyloxycarbonyl-phenylacetic acid.

Melting point: 85°-88° C. (acetone/petroleum ether)

Calculated: C 71.31; H 7.04; N 4.89. Found: C 71.64; H 7.10; 4.77.

EXAMPLE 56 Ethyl4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxy-benzoate

Prepared analogously to Example 23 from(2-piperidino-phenyl)-glycine-ethylester-dihydrochloride and4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.

Melting point: 107°-110° C. (petroleum ether)

Calculated: C 66.65; H 6.88; N 5.98. Found: C 66.60; H 6.86; 6.03.

EXAMPLE 57 Ethyl2-ethoxy-4-[(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

First, 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid (2.52 g, 10 mmol) andN,N'-carbonyldiimidazole (1.62 g, 10 mmol) are heated to 70° C. for 45minutes in absolute tetrahydrofuran (15 ml). A solution of2-hydroxy-1-(2-piperidino-phenyl)-1-ethylamine (2.07 g, 9.4 mmol)[prepared by reducing (2-piperidino-phenyl)-glycine-ethylester withlithium aluminium hydride in ether] in absolute tetrahydrofuran (7 ml)is added thereto and the mixture is refluxed for 1 hour. After standingovernight it is diluted with ethyl acetate (50 ml) and shaken twice withwater (30 ml). The organic phase is dried and filtered and concentratedby evaporation in vacuo. The evaporation residue is purified by columnchromatography on silica gel (chloroform/methanol=19/1).

Yield: 2.4 g,

Melting point: 127°-128° C. (acetone)

Calculated: C 68.70; H 7.54; N 6.16. Found: C 68.80; H 7.58; N 6.15.

EXAMPLE 58 Benzyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 29 from3-ethoxy-4-benzyloxycarbonyl-phenylacetic acid and2-hydroxy-1-(2-piperidino-phenyl)-1-ethylamine.

Melting point: 89°-91° C. (acetone/ether)

Calculated: C 72.07; H 7.02; N 5.42. Found: C 72.10; H 7.15; N 5.29.

EXAMPLE 592-Ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Ethyl2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(0.45 g, 0.9 mmol) in ethanol (5 ml) is stirred together with 1N sodiumhydroxide solution (2.7 ml) for 2 hours at 50° C. Then 1N hydrochloricacid (2.7 ml) is added and the mixture is concentrated by evaporation invacuo. The evaporation residue is partitioned between water andchloroform. The combined chloroform extracts are shaken once with water,then the organic phase is dried, filtered and evaporated down in vacuo.The evaporation residue is crystallized with ether.

Yield: 0.27 g,

Melting point: 222°-225° C. (decomp.)

Calculated: C 65.44; H 6.41; N 6.36. Found: C 65.58; H 6.59; N 6.28.

EXAMPLE 604-[N-(α-Carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxy-benzoicacid

Prepared analogously to Example 31 by alkaline saponification of ethyl4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxy-benzoate.

Melting point: 220°-228° C.

Calculated: C 64.07; H 5.87; N 5.79. Found: C 63.84; H 5.95; N 7.13.

EXAMPLE 612-Ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 31 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoateand purification by column chromatography on silica gel(chloroform/ethanol=95/5).

Melting point: 80°-81° C. (decomp., sintering from 75° C.)

Calculated: molecular peak m/e=426 Found: molecular peak m/e=426

EXAMPLE 62 Ethyl2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoate

Ethyl2-ethoxy-4-[N-(α-ethoxycarbonyl-2piperidino-benzyl)-aminocarbonylmethyl]-benzoate(0.45 g, 0.9 mmol) in ethanol (5 ml) is stirred together with 1N sodiumhydroxide solution (0.90 ml) for 4 hours at ambient temperature. Then 1Nhydrochloric acid (0.90 ml) is added and the mixture is evaporated downin vacuo. The residue is partitioned between water and chloroform, thechloroform solution is dried and filtered and concentrated byevaporation in vacuo. The evaporation residue is purified by columnchromatography on silica gel (chloroform/ethanol=5/1).

Yield: 0.23 g,

Melting point: 177°-180° C. (ether)

Calculated: C 66.65; H 6.88; N 5.98. Found: C 66.65; H 7.11; N 5.79.

EXAMPLE 63 Ethyl4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonyl-methyl]-2-hydroxy-benzoate

Prepared analogously to Example 34 by alkaline saponification of ethyl4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxybenzoate.

Melting point: 156°-159° C. (ether)

Calculated: C 65.44; H 6.41; N 6.36. Found: C 65.66; H 6.38; N 6.33.

EXAMPLE 64 Benzyl2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 34 by alkaline saponification of benzyl2-ethoxy-4-[-(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein dioxan.

Melting point: 140°-142° C.

Calculated: C 70.17; H 6.46; N 5.28. Found: C 70.21; H 6.50; N 5.31.

EXAMPLE 65 Ethyl2-ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

To a solution of ethyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(0.227 g, 0.5 mmol) and absolute triethylamine (0.126 ml, 0.9 mmol) inabsolute chloroform (3 ml), a solution of acetyl chloride (0.063 ml, 0.9mmol) in absolute chloroform (1 ml) is added dropwise. After 4 days'stirring at ambient temperature the mixture is diluted with chloroform,washed with dilute aqueous sodium bicarbonate solution, the chloroformsolution is dried and filtered and evaporated down in vacuo. Theevaporation residue is purified by column chromatography on silica gel(chloroform/acetone=4/1).

Yield: 0.17 g,

Melting point: 107°-109° C. (ether/petroleum ether)

Calculated: C 67.72; H 7.31; N 5.64. Found: C 67.70; H 7.48; N 5.74.

EXAMPLE 66 Benzyl2-ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 37 from benzyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatewith acetyl chloride.

Calculated: molecular peak m/e=558

Found; molecular peak m/e=558

EXAMPLE 67 Benzyl2-ethoxy-4-[N-(α-propionyloxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 37 from benzyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatewith propionyl chloride.

Melting point: 73°-74° C.

Calculated: C 71.31; H 7.04; N 4.89. Found: C 71.20; H 7.10; N 4.61.

EXAMPLE 682-Ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

A solution of benzyl2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(0.140 g, 0.25 mmol) in ethanol (1.4 ml) is hydrogenated with 10%palladium/charcoal (0.03 g) for 4.5 hours at 50° C. under 5 bar ofhydrogen. The mixture is filtered, evaporated down in vacuo and theevaporation residue is purified by column chromatography on silica gel(chloroform/methanol=10/1).

Yield: 0.041 g,

Melting point: 115°-118° C. (petroleum ether)

Calculated: molecular peak m/e=468 Found: molecular peak m/e=468

EXAMPLE 602-Ethoxy-4-[N-(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 40 by catalytic hydrogenation of benzyl2-ethoxy-4-[-(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein methanol.

Melting point: 147°-150° C. (decomp.) (ether)

Calculated: C 66.06; H 6.65; N 6.16. Found: C 66.28; H 6.56; N 5.90.

EXAMPLE 702-Ethoxy-4-[N-(α-n-propoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 40 by catalytic hydrogenation of benzyl2-ethoxy-4-[N-(α-n-propoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein n-propanol.

Melting point: 122-°125° C. (ether/petroleum ether=1/1).

Calculated: C 67.20; H 7.10; H 5.80. Found: C 67.39; H 7.24; H 5.78.

EXAMPLE 712-Ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 40 by catalytic hydrogenation of benzyl2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein isopropanol.

Melting point: 149°-151° C. (acetone/petroleum ether)

Calculated: C 67.20; H 7.10; N 5.80. Found: C 67.50; H 6.99; N 5.78.

EXAMPLE 722-Ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 40 by catalytic hydrogenation of benzyl2-ethoxy-4-[N-(α-acetoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein ethanol.

Calculated: molecular peak m/e=468 Found: molecular peak m/e=468

EXAMPLE 732-Ethoxy-4-[N-(α-propionyloxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 40 by catalytic hydrogenation of benzyl2-ethoxy-4-[N-(α-propionylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoatein ethanol.

Melting point: 64°-67° C. (ethanol/water).

Calculated: molecular peak m/e=482 Found: molecular peak m/e=482

EXAMPLE 742-Hydroxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Boron tribromide (0.04 ml, 0.414 mmol) is added at -20° C. with theexclusion of moisture to a stirred solution of2-ethoxy-4-[N-(α-isopropoxy-carbonyl-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoicacid (0.20 g, 0.414 mmol) in 1,2-dichloroethane (5 ml). The mixture isallowed to come up to ambient temperature and is then stirred for 2hours. It is poured into isopropanol, the mixture is concentrated byevaporation in vacuo, water is added and the mixture is extracted withchloroform. The organic extract is dried and filtered and evaporateddown in vacuo. The evaporation residue is purified by columnchromatography on silica gel (chloroform methanol/glacial aceticacid=5/1/0.01%.

Yield: 0.14 g,

Melting point: molecular peak m/e=454 Found: molecular peak m/e=454

EXAMPLE 75 Ethyl2-ethoxy-4-[N-(α-ethoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Ethyl2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(0.64 g, 1.4 mmol) is added with stirring at ambient temperature tosodium hydride (0.061 g, 1.4 mmol) (55% in oil) in absolutetetrahydrofuran (6.4 ml). The mixture is stirred for 1 hour, then ethyliodide (0.113 ml, 1.4 mmol) is added and the mixture is stirred for afurther 16 hours at ambient temperature. Then ethanol (2 ml) is addedand the mixture is evaporated down in vacuo. The evaporation residue ispartitioned between chloroform and water. The organic phase is washedtwice with water, dried, filtered and concentrated by evaporation invacuo. The evaporation residue is purified by column chromatography onsilica gel (chloroform/acetone=17/3).

Yield: 0.05 g,

Melting point: 85°-87° C. (petroleum ether)

Calculated: molecular peak m/e=482 Found: molecular peak m/e=482

EXAMPLE 762-Ethoxy-4-[N-(α-ethoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 31 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-ethoxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Calculated: molecular peak m/e=454 Found: molecular peak m/e=454

EXAMPLE 774-[N-(α-Carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-2-hydroxy-benzoicacid

Prepared analogously to Example 46 by reacting2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid with 2.5 equivalents of boron tribromide in methylene chloride.

Melting point: 220°-230° C. (water)

Calculated: C 64.07; H 5.87; N 6.79. Found: C 64.21; H 5.99; N 6.81.

EXAMPLE 783-[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionitrile

Magnesium chips (0.11 g, 4.5 mmol) are added to2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamicacid nitrile (0.05 g, 0.11 mmol) in methanol (1.1 ml) and the mixture isstirred for 45 minutes at 25° C. and for 1 hour at 0° C. It is thencooled to 0° C. and mixed with of 1N hydrochloric acid (4.5 ml). It isdiluted with water, filtered over kieselguhr and extracted withchloroform. The chloroform extract is washed with aqueous sodiumbicarbonate solution, dried and filtered and concentrated by evaporationin vacuo. The evaporation residue is purified by column chromatographyon silica gel (chloroform/ethyl acetate=9/1).

Yield: 0.015 g,

Melting point: 102°-104° C. (petroleum ether)

Calculated: molecular peak m/e=447 Found: molecular peak m/e=447

EXAMPLE 79[2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-phenyl]-acetonitrile

Prepared analogously to Example 1 from2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzylchloride with sodium cyanide.

Melting point: 135°-136° C.

Calculated: C 75.13; H 8.33; N 9.39. Found: C 75.12; H 8.18; N 9.18.

EXAMPLE 80 Ethyl2-ethoxy-4-[N-(α-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 fromα-cyclopropylmethyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 126°-127° c.

Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.85; H 7.74; N 5.84.

EXAMPLE 812-Ethoxy-4-[N-(α-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid hemihydrate

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 103°-104° C.

Calc. (×0.5 H₂ O): C 70.55; H 7.68; N 6.10. Found: C 70.67; H 7.67; N6.37.

EXAMPLE 82 Ethyl2-ethoxy-4-[N-(α-cyclobutylmethyl]-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 is fromα-cyclobutylmethyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid.

Melting point: 116°-118° C.

Calculated: C 73.14; H 8.18; N 5.69. Found: C 73.14; H 8.32; N 5.64.

EXAMPLE 832-Ethoxy-4-[N-(α-cyclobutylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-cyclobutylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 140°-142° C.

Calculated: C 72.39; H 7.81; N 6.03. Found: C 72.15; H 7.79; N 5.97.

EXAMPLE 84 Ethyl2-ethoxy-4-[N-(α-cyclopentylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 fromα-cyclopentylmethyl-2-piperidino-benzylamine and3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid.

Melting point: 120°-121° C.

Calculated: C 73.49; H 8.36; N 5.53. C 73.31; H 8.55; N 5.39.

EXAMPLE 852-Ethoxy-4-[N-(α-cyclopentylmethyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethox-4-[N-(α-cyclopentyl-methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 85°-88° C.

Calculated: C 72.77; H 8.00; N 5.85.

Found C 72.50; H8.02; N 6.03.

EXAMPLE 86 Ethyl2-ethoxy-4-[N-(2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from2-piperidino-α-(tetrahydrofuran-2-yl-methyl)benzylamine and3-ethoxy-4-ethoxycarbonyl-phenyl-acebic acid.

Melting point: 111°-113° C. Calculated: C 70.84; H 7.93; N 5.51. Found:C 70.76; H 7.73; N 5.51.

EXAMPLE 872-Ethoxy-4-[N-(2-piperidino-α-(tetrahydrofuran-2-ylmethyl)-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzyl)-amino-carbonylmethyl]-benzene.

Melting point: 121°-123° C.

Calculated: C 69.98; H 7.55; N 5.83.

Found: C 69.90; H 7.78; N 5.71.

EXAMPLE 88 Ethyl2-ethoxy-4-[N-(α-cycloheptylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from α-cycloheptylmethyl-benzylamineand 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 96°-98° C.

Calculated: C 74.12; H 8.67; N 5.24.

Found C 74.40; H 8.87; N 5.39.

EXAMPLE 892-Ethoxy-4-[N-(α-cycloheptylmethyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-cycloheptylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 127°-130° C.

Calculated: C 73.49; H 8.36; N 5.53. Found: C 73.54; H 8.62; N 5.47.

EXAMPLE 90 Ethyl2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

a) Ethyl2-ethoxy-4-[N-(α-(cyclohexyl-methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 fromα-cyclohexylmethyl-(2-piperidino-phenyl)-ketimine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 85°-88° C.

Calculated: C 74.10; H 8.16; N 5.10.

Found: C 74.37; H 8.00; N 5.45.

According to the 80 MHz-¹ H-NMR spectrum (CDCl₃) there is a mixture ofE/Z=1/2. (Olefinic H: (E) D 6.26, (Z) 5.42 ppm].

b) Ethyl2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 12 by catalytic hydrogenation of ethyl2-ethoxy-4-[N-(α-(cycohexylmethylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Melting point: 95°-97° C. Calculated: C 73.83; H 8.52; N 5.38. Found: C73.92; H 8.74; N 5.29.

EXAMPLE 912-Ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoicacid

a)2-Ethoxy-4-[N-(α-(cyclohexyl-methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(α-(cyclohexyl-methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate.

Melting point: 95°-100° C.

Calculated: C 73.44; H 7.81; N 5.71. Found: C 73.38; H 7.73; N 5.75.

b)2-Ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 12 by catalytic hydrogenation of2-ethoxy-4-[N-(α-(cyclohexyl-methylidene)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid.

Melting point: 154°-156° C.

Calculated: C 73.14; H 8.18; N 5.69. Found: C 73.31; H 8.25; N 5.71.

EXAMPLE 92 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from1-(2-piperidino-phenyl)-3-buten-1-yl-amine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 110°-112° C.

Calculated: C 72.39; H 7.81; N 6.03. Found: C 72.10; H 7.66; N 5.94.

EXAMPLE 932-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)-aminocarbonylmethyl]-benzoate.

Melting point: 92°-95° C. Calculated: C 71.53; H 7.39; N 6.42. Found: C71.27; H7.42; N 6.42.

EXAMPLE 94 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-1-yl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 From3-methyl-1-(2-piperidino-phenyl)-3-buten-1-yl)-amine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 126°-128° C.

Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.82; H 8.22; N 5.78.

EXAMPLE 952-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-1-yl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-1-yl)-aminocarbonylmethyl]-benzoate.

Melting point: 64°-66° C.

Calculated; C 71.97; H 7.61; N 6.22. Found: C 71.70; H 7.50; N 5.98.

EXAMPLE 96 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-2-buten-1-yl)-aminocarbonylmethyl]-benzoate[with 25% of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate]

Prepared analogously to Example 19 from3-methyl-1-(2-piperidino-phenyl)-2-buten-1-yl-amine [containing 25% of3-methyl-1-(2-piperidino-phenyl)-1-butylamine] and3-ethoxy--4-ethoxycarbonylphenylacetic acid.

Melting point: 141°-142° C.

Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.60; H 7.77; N 5.73.

The mixing ratio of 75/25 is obtained from the corresponding ratio ofintensities of the particularly characteristic signals in the 400 MHz-¹H-NMR spectrum (CDCl₃). The position of the signals is:3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH₃ : 1.64 (s) and1.77 (s). benzylic ##STR18## 6.00 (t), benzylic CH₂ --; 3.52 ppm (s)3-methyl-1-butyl compound: CH₃ : 0.90 (d), benzylic ##STR19## 5.35 (m),benzylic --CH₂ --: 3.54 ppm (s).

EXAMPLE 972-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-2-buten-1-yl)-aminocarbonylmethyl]-benzoicacid [containing 25% of2-ethoxy-4-[N-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid]

Prepared analogously to Example 21 by alkaline saponification of thecorresponding ethyl ester mixture from Example 68.

Melting point: 154°-156° C.

Calculated: C 71.97; H 7.61; N 6.22. Found: C 71.80; H 7.57; N 5.98.

EXAMPLE 98 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from1-(2-piperidino-phenyl)-3-butyn-1-yl-amine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 86°-90° C.

Calculated: C 72.70; H 7.41; N 6.06. Found: C 72.60; H 7.40; N 6.04.

EXAMPLE 992-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)-aminocarbonylmethyl]-benzoate.

Melting point: 66°-69° C.

Calculated: C 71.87; H 6.97; N 6.45. Found: C 71.60; H 6.95; N 6.38.

EXAMPLE 100 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from1-(2-piperidino-phenyl)-4-penten-1-yl-amine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.

Melting point: 117°-12020 C.

Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.73; H 7.97; N 6.07.

EXAMPLE 1012-Ethoxy-4-(N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonylmethyl]benzoate.

Melting point: 82°-85° C. Calculated: C 71.97; H 7.61; N 6.22. Found: C71.97; H 7.59; N 5.98.

EXAMPLE 102 Ethyl2-ethoxy-4-[N-(1-(2-piperidino-α-(tetrahydropyran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoate

Prepared analogously to Example 19 from2-piperidino-α-(tetrahydropyran-2-yl-methyl)benzylamine and3-ethoxy-4-ethoxycarbonylphenylacetic acid.

Melting point: 82°-85° C. Calculated: C 71.24; H8.10; N 5.36. Found: C71.28; H 7.96; N 5.29.

EXAMPLE 1032-Ethoxy-4-[N-(1-(2-piperidino-α-(tetrahydropyran-2-yl-methyl)-benzyl)-aminocarbonylmethyl]-benzoicacid

Prepared analogously to Example 21 by alkaline saponification of ethyl2-ethoxy-4-[N-(1-(2-piperidino-α-(tetrahydropyran-2-yl-methyl)-benzyl)aminocarbonyl-methyl]-benzoate.

Melting point: 140°-142° C. (sinters from 70° C., partial softening at105° C.)

Calculated: C 70.42; H 7.74; N 5.66. Found: H 7.88; N 5.40.

Ethyl2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

At 23°-25° C., a solution of ethyl 2-ethoxy-4-cyanomethyl-benzoate (2.35g, 10 mmol) and α-cyclohexylmethyl-2-piperidino-benzyl alcohol (2.88 g,10 mmol) in o-dichlorobenzene (15 ml) is added dropwise to a mixture ofconcentrated sulphuric acid (15 ml) and o-dichlorobenzene (15 ml). Themixture is stirred for 2 hours at ambient temperature. Theo-dichlorobenzene phase is then separated off and the residue is addedto ice. After being made alkaline with soda solution, it is extractedwith chloroform. The extracts are dried over sodium sulphate andconcentrated by evaporation. The residue is purified by columnchromatography on silica gel (toluene/acetone=10/1). Yield: 1.1 g

Melting point: 95°-97° C.

Calculated: C 73.81 H 8.52 N 5.38 Found: C 73.95; H 8.64; N 5.42.

EXAMPLE 105 Benzyl2-ethoxy-4-[N-α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate

Potassium carbonate (0.28 g, 2 mmol) is added to a solution of benzyl2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate(1.06 g, 2 mmol) in anhydrous dimethyl formamide (8 ml). The mixture isstirred for 10 minutes at ambient temperature, then methyl iodide (0.125ml, 2 mmol) is added and the resulting mixture is stirred overnight atambient temperature. It is filtered and the filtrate is concentrated byevaporation to dryness in vacuo. The evaporation residue is partitionedbetween aqueous sodium bicarbonate solution (pH=9) and methylenechloride. The organic phase was poured over sodium sulphate, filteredand concentrated by evaporation in vacuo. The evaporation residue ispurified by column chromatography on silica gel (toluene/acetone=4/1)and crystallised from ether/petroleum ether.

Yield: 0.56 g,

Melting point: 100°-102° C.

Calculated: C 70.57; H 6.66; N 5.14. Found: C 70.69; H 6.71; N 5.29.

EXAMPLE 106 (S)2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoicacid

a) (S)-3-Methyl-1-(2-piperidino-phenyl)-1-butylamine

Equimolar quantities of racemic3-methyl-1-(2-pieridinophenyl)-1-butylamine and of N-acetyl-L-gluatmicacid were refluxed in aceton, whereby methanol was added in such anamount to yield a clear solution.

After cooling over night up to 20° C., the obtained crystals weresuction filtered and twice washed with aceton cooled to -15° C. Theobtained product [M.p.: 163°-166° C.: [α]_(D) ²⁰ =+0,286° (c=1 inmethanol)[ was recrystallised from aceton under addition of methanol,whereby (S)-3-methyl-1-[2-piperidino-phenyl)-1-butylamine asN-acetyl-L-glutamic acid addition salt was obtained in a yield of 60,4%of theory.

M.p.: 168°-171° C.

[α]₂₀ ^(D) =+0,356° (c=1 in methanol)

The free amine was obtained after reacting with sodium hydroxidesolution.

b) (S) Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate

Prepared from (S)-3-Methyl-1-(2-piperidino-phenyl)-1-butylamine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example 1.

Yield: 77% of theory,

M.p.: 121°-123° C. (petroleum ether/aceton=7/1) [α]_(D) ²⁰ =+7.82° (c=1in methanol)

c) (S)2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoicacid

Prepared from (S) Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoateby saponification analogously to Example 4.

Yield: 75,9% of theory,

M.p.: 102°-104° C. (petroleum ether/toluene),

[α]₂₀ ^(D) =+7.80° (c=1,025 in methanol).

The compounds of the present invention, that is, those embraced byformula I above, including forms (A), (B) and (C) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}aminocarbonylmethyl]-benzoicacid, their enantiomers and their non-toxic, pharmacologicallyacceptable salts formed with inorganic or organic acids or bases, haveuseful pharmacodynamic properties. More particularly, they have afavorable effect on the intermediate metabolism and exhibitshypoglycemic activity in warm-blooded animals such as rats.

The hypoglycemic activity of the compounds of the instant invention wasascertained by the standard pharmacological test method described below,and the table which follows shows the results of this test for a fewrepresentative species of the genus, where

A=2-methoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}-aminocarbonylmethyl]-benzoicacid,

B=2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid,

C=2-methoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid,

D=2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid,

E==(+)-2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid,

F=2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-ethyl}aminocarbonylmethyl]-benzoicacid,

G=sodium2-ethoxy-4-[N-{1-(2-pyrrolidino-phenyl)-1-butyl}aminocarbonylmethyl]-benzoate,

H=2-ethoxy-4-[N-{1-(2-hexamethyleneimino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid

I=2-methoxy-4-(N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid,

K=2-n-propoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoicacid,

L=2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-pentyl}-aminocarbonylmethyl]-benzoicacid.

M=2-ethoxy-4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoicacid,

N=form (B) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid,

O=[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-acetonitrile,

P=[2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]acetonitrile,

Q=2-ethoxy-4-[N-(α-cyclohexylmethyl-2-piperidino-benzyl)aminocarbonylmethyl]-benzoicacid,

R=2-ethoxy-4-(N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid,

S=2-ethoxy-4-[N-(α-methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzoicacid,

T=2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminobonylmethyl]benzoicacid,

U=2-ethoxy-4-[N-(α-cyclopropylmethyl-2-piperidino-benzyl)-aminocarbonylmethyl]benzoicacid,

V=2-ethoxy-4-[N-(α-(tetrahydrofuran-2-yl-methyl)-2-piperidino-benzyl]-aminocarbonylmethyl)benzoicacid,

W=2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-buten-1-yl)aminocarbonylmethyl]benzoicacid,

X=2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-3-buten-1-yl)-aminocarbonylmethyl]benzoicacid and

Y=2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-butyn-1-yl)aminocarbonylmethyl]benzoicacid,

Test for Hypoglycemic Activity

The hypoglycemic activity of the test compounds was ascertained onfemale rats of a particular strain weighing from 180-220 g which hadbeen fasted for 24 hours before the start of the test. The testcompounds were suspended in 1.5% methyl cellulose immediately before thestart of the test and administered by esophageal tube.

Blood samples were takes immediately before the administration of thetest compound and 1, 2, 3 and 4 hours afterwards, in each case from theretroorbital Venous plexus. 50 μl of each sample were deproteinated with0.5 ml of 0.33 N perchloric acid and centrifuged. The glucose in thesupernatant fluid was measured using the hexokinase method with the aidof an analytical photometer. The statistical evaluation was made usingthe t-test according to Student with p=0.05 as the limit ofsignificance.

The following tables show the change in glucose content in percentcompared with the control:

                  TABLE I                                                         ______________________________________                                        1 mg/kg             0.5 mg/kg                                                 Compound                                                                              1      2      3    4 h  1    2    3    4 h                            ______________________________________                                        A       -37    -46    -23  -14                                                B       -38    -49    -38  -33  -43  -36  -34  -35                            C       -38    -41    -38  -34                                                D       -42    -54    -37  -34                                                E                               -40  -39  -36  -36                            F       -44    -44    -40  -30                                                G                               -40  -33  -30  -17                            H                               -42  -34  -18  n.s.                           I                               -42  -39  -37  -30                            K                               -34  -36  -24  n.s.                           L                               -42  -45  -38  -39                            M       -44    -41    -35  -27                                                O       -29    -37    -35  -34                                                P       -12    -10    -14  - 14                                               Q                               -22  -47  -45  -45                            R       -33    -17    n.s. n.s.                                               S       -42    -35    -28  -18                                                T       -36    -21    -18  n.s.                                               U                               -45  -45  -36  -36                            V                               -46  -25  -13  -10                            W                               -42  -39  -28  -35                            X                               -44  -41  -31  -28                            Y                               -33  -18  -11  n.s.                           ______________________________________                                         n.s. = not statistically significant                                     

                  TABLE II                                                        ______________________________________                                                   0.1 mg/kg                                                          Compound     1      2          3    4 h                                       ______________________________________                                        N            -38    -44        -41  -40                                       ______________________________________                                    

In the tests for hypoglycemic activity, no toxic side effects wereobserved, even at a dosage of 10 mg/kg p.o., with any of thesecompounds.

The novel compounds are virtually non-toxic; for example, after a singledose of 2,000 mg/kg p.o. (suspension in 1% methyl cellulose) ofcompounds B and D to 5 male and 5 female mice, only one animal in thisgroup died during the observation period of 14 days.

The toxic effect of a single dose of compound N administered orally(suspended in 1% methyl cellulose) was tested in male and female mice ofour own strain weighing from 20-26 g over an observation period of 14days.

                  TABLE III                                                       ______________________________________                                        Compound  Approximate acute toxicity                                          ______________________________________                                        N         >1000 mg/kg p.o. (0 out of 6 animals died)                          ______________________________________                                    

By virtue of their pharmacological properties, the compounds of thepresent invention are useful for the treatment of diabetes mellitus.

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally or parenterally as activeingredients in customary pharmaceutical compositions, that is,compositions consisting essentially of an inert pharmaceutical carrierand an effective amount of the active ingredient, such as tablets,coated pills, capsules, wafers, powders, solutions, suspensions,emulsions, syrups and the like. An effective amount of the compounds ofthe present invention is from 0.014 to 0.71 mgm/kg body weight,preferably 0.035 to 0.29 mgm/kg body weight, once or twice daily.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of using the invention. Theparts are parts by weight unless otherwise specified.

EXAMPLE 107 Tablets containing 5 mg of2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid, form (B)

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        Active ingredient  (1)   5.0 parts                                            Corn starch        (2)   62.0 parts                                           Lactose            (3)   48.0 parts                                           Polyvinylpyrrolidone                                                                             (4)   4.0 parts                                            Magnesium stearate (5)   1.0 parts                                                                     120.0 parts                                          ______________________________________                                    

Preparation

Ingredients (1), (2), (3) and (4) are mixed together and moistened withwater. The moist mixture is passed through a 1.5 mm mesh screen anddried at about 45° C. The dry granulate is passed through a 1.0 mm meshscreen and mixed with ingredient (5). The finished mixture is compressedinto 120 mg-tablets.

EXAMPLE 108 Coated tablets containing 2.5 mg of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid, form (A)

The tablet core composition is compounded from the followingingredients:

    ______________________________________                                        Active ingredient  (1)   2.5 parts                                            Potato starch      (2)   44.0 parts                                           Lactose            (3)   30.0 parts                                           Polyvinylpyrrolidone                                                                             (4)   3.0 parts                                            Magnesium stearate (5)   0.5 parts                                                                     80.0 parts                                           ______________________________________                                    

Preparation

Ingredients (1), (2), (3) and (4) are thoroughly mixed and moistenedwith water. The moist mass is passed through a 1 mm-mesh screen, driedat about 45° C., and the granulate is then passed through the samescreen. After ingredient (5) has been added, convex 80 mg-tablet coresare compressed in a tablet-making machine. The tablet cores thusproduced are covered in known manner with a coating consistingessentially of sugar and talc. The finished tablets are polished withwax. Weight of each coated tablet: 120 mg.

EXAMPLE 109 Tablets containing 10 mg of2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoicacid

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        Active ingredient 10.0 parts                                                  Powdered lactose  70.0 parts                                                  Corn starch       31.0 parts                                                  Polyvinylpyrrolidone                                                                             8.0 parts                                                  Magnesium stearate                                                                               1.0 parts                                                                    120.0 parts                                                 ______________________________________                                    

Preparation

The mixture of active ingredient, lactose and corn starch is moistenedwith a 20% solution of polyvinylpyrrolidone in water. The moist mass ispassed through a 1.5 mm mesh screen and dried at 45° C. The driedgranulate is passed through a 1 mm mesh screen and is homogeneouslymixed with magnesium stearate. The composition is compressed into 120mg-tablets.

EXAMPLE 110 Coated tablets containing 5 mg of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]benzoicacid

The tablet core composition is compounded from the followingingredients:

    ______________________________________                                        Active ingredient   5.0 parts                                                 Secondary calcium phosphate                                                                       70.0 parts                                                Corn starch         50.0 parts                                                Polyvinylpyrrolidone                                                                              4.0 parts                                                 Magnesium stearate  1.0 parts                                                                     130.0 parts                                               ______________________________________                                    

Preparation

The mixture of active ingredient, calcium phosphate and corn starch ismoistened with a 15% solution of polyvinylpyrrolidone in water. Themosit mass is passed through a 1 mm mesh screen, dried at 45° C. andthen passed through the same screen. After adding the magnesiumstearate, 130 mg-tablet cores are compressed from the mixture.

A coating of sugar and talc is applied in known manner to the cores thusproduced. The finished coated tablets are polished with wax.

Weight of coated tablet: 180 mg.

Any one of the other compounds embraced by formula I, including forms(A), (B) and (C) of2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoicacid, an enantiomer thereof or a non-toxic, pharmacologically acceptablesalt thereof may be substituted for the particular active ingredient inExamples 29 through 32. Likewise, the amount of active ingredient inthese illustrative examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and the various changes and modifications may be madewithout departing from the spirit of the invention of the scope of theappended claims.

(S)(+)-2-Ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoicacid, pharmaceutical compositions containing this compound and processesfor the preparation thereof

EP-B-147850 describes inter alia the racemate of2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoicacid (Code No.: AG-EE 388 ZW) of the formula ##STR20## and EP-B-207331describes two other polymorphous forms of this compound. This compoundand the physiologically acceptable salts thereof have valuablepharmacological properties, namely an effect on the intermediatemetabolism, but more particularly the effect of lowering blood sugar.

The two enantiomers of this compound, namely(S)(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoicacid (Code No.: AG-EE 623 ZW) and(R)(-)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoicacid (Code No.: AG-EE 624 ZW) have been tested for their bloodsugar-lowering effect on female rats, bred by the applications, weighing180 to 220 g which had been kept fasting 24 hours before the start ofthe experiment. The substances to be investigated were suspended in 1.5%methylcellulose immediately before the start of the test andadministered into the oesophagus.

Blood samples were taken immediately before administration of thesubstance and 1, 2, 3, 4, 5 and 6 hours thereafter, from theretroorbital venous plexus, in each case. 50 μl of blood weredeproteinated with 0.5 ml of 0.33 N perchloric acid and centrifuged.Glucose was measured in the supernatant by the hexokinase method usingan analytical photometer. The statistical evaluation was carried outusing the Student's t-test with p=0.05 as the limit of significance.

Table 1 which follows contains the statistically significant values aspercentage deviation from the control:

                  TABLE 1                                                         ______________________________________                                        Substance   1      2       3    4     5    6 hours                            ______________________________________                                        AG-EE 623 ZW                                                                              -17    -36     -37  -32   -35  -35                                0.015 mg/kg p.o.                                                              AG-EE 624 ZW                                                                              n.s.   n.s.    n.s. n.s.  --   --                                 1.0 mg/kg p.o.                                                                ______________________________________                                         n.s. = statistically not significant                                          -- = not measured                                                        

It is found that the (S)-enantiomer (AG-EE 623 ZW) is the effectiveenantiomer and its effect lasts longer than 6 hours in the rat.

On the basis of these findings in the rat, it seems appropriate to useexclusively AG-EE 623 ZW in humans, thereby reducing the dose by 50%,compared with the dose of AG-EE 388 ZW. This has been confirmed inhumans, as explained hereinafter. However, it was also found in thehuman studies that AG-EE 623 ZW has surprising pharmacokineticproperties which could not have been foreseen on the basis of the AG-EE388 ZW data. AG-EE 623 ZW thus has surprising therapeutic advantagesover the racemate AG-EE 388 ZW.

More specifically, the studies which follow were carried out on healthymale volunteers in whom the levels of glucose and active substance inthe course of time were determined:

In study 1 (randomised, double blind, group comparison), 12 testsubjects, in a fasting state, were given in the morning a placebocapsule or a capsule containing 2 mg of micronised AG-EE 388 ZW. 5.5hours after oral administration, a standard lunch (L) was eaten, 7 hoursafter administration a snack (S) was eaten and 10 hours afteradministration a standard evening meal (D) was eaten. Blood samples weretaken at different times. The glucose concentrations were determinedfrom whole blood using the hexokinase method (see above). Theconcentrations of AG-EE 388 ZW were determined from the plasma using anon-stereoselective HPLC method with electrochemical detection and adetection limit of 5 ng/ml (see A. Greischel, K. Beschke, H. Rapp and W.Roth in Journal of Chromatography, Biomedical Applications entitled"Quantitation of the New Hypoglycemic Agent AG-EE 388 ZW in Human Plasmaby Automated High-Performance Liquid Chromatography with ElectrochemicalDetection"; submitted).

Table 2 which follows contains the average glucose levels found in thesubject group as a percentage deviation from the placebo group as wellas the average AG-EE 388 ZW concentrations in ng/ml together with thestandard deviation (SD) in the subject group.

                  TABLE 2                                                         ______________________________________                                        (Study 1)                                                                     Time after Glucose     Concentration                                          administration                                                                           [%] deviation                                                                             AG-EE 388 ZW [ng/ml]                                   [hours]    from placebo                                                                              mean       SD                                          ______________________________________                                        0          n.s.         0.0       0.0                                         0.50       n.s.        55.8       32.9                                        0.75        -9         82.9       17.9                                        1.00       -17         82.8       15.3                                        1.50       -27         64.7       8.2                                         2.00       -24         58.3       12.0                                        2.50       -19         --         --                                          3.00       n.s.        29.4       7.6                                         4.00       -24         16.3       6.9                                         5.00        -9          9.0       6.2                                         5.50-(L)   n.s.        --         --                                          6.00       n.s.         4.2       4.5                                         7.00-(S)   n.s.        --         --                                          8.00        -5          1.2       2.9                                         9.00       n.s.        --         --                                          10.00-(D)  n.s.         0.0       0.0                                         ______________________________________                                         n.s. = statistically not significant                                          -- = not measured                                                             (L) = lunch                                                                   (S) = snack                                                                   (D) = dinner                                                             

It is found that the level of active substance reaches the detectionlimit after 5 hours and that the duration of activity of AG-EE 388 ZW isabout 5 hours. There is thus a good correlation between the plasma levelcurve of AG-EE 388 ZW and the blood sugar-lowering effect.

In study 2 (randomised, open, crossover) 12 test subjects, in a fastingstate, were given in the morning either a capsule containing 2 mg ofmicronised AG-EE 388 ZW or a spray-dried tablet containing 2 mg of AG-EE388 ZW. 2 hours after oral administration a standard breakfast (B) waseaten, 5 hours after administration a standard lunch (L) was eaten and10.5 hours after administration a standard evening meal (D) was eaten.Blood samples were taken at various times. The glucose was measured inwhole blood and the concentration of the active substance was measuredin the plasma as in study 1.

Table 3 which follows contains the average glucose levels found inmmol/1 after administration of capsules or tablets together with thestandard deviations and the average AG-EE 388 ZW concentrations in ng/mltogether with the standard deviations (SD).

                  TABLE 3                                                         ______________________________________                                        (Study 2)                                                                              Glucose         Concentration                                        Time after                                                                             [mmol/l]        AG-EE 388 ZW [ng/ml]                                 administration                                                                         Capsule   Tablet    Capsule Tablet                                   [hours]  mean   SD     mean SD   mean SD   mean SD                            ______________________________________                                        0        5.0    0.2    4.9  0.3   0.0 0.0   0.0  0.0                          0.20     5.0    0.3    5.0  0.4   0.9 3.1  15.0 14.3                          0.33     4.9    0.3    4.9  0.4  17.5 12.3 55.6 36.0                          0.50     4.8    0.3    4.6  0.5  44.9 21.5 55.6 34.6                          0.75     4.6    0.3    4.4  0.5  66.4 20.6 83.5 25.5                          1.00     4.4    0.4    4.1  0.5  73.7 15.5 81.3 22.5                          1.50     3.9    0.6    3.8  0.4  65.1 16.9 65.9 17.5                          2.00-(B) 3.7    0.3    3.8  0.2  50.8 13.5 51.3 14.9                          3.00     4.4    1.0    4.7  0.9  27.9 8.1  32.4 12.8                          4.00     4.0    0.6    4.2  0.3  16.8 5.1  19.1  8.0                          5.00-(L) 4.2    0.4    4.2  0.5  12.2 3.4  13.2  6.1                          6.00     4.8    0.8    5.2  0.7   7.8 4.3   9.5  5.7                          9.00     5.0    0.3    5.0  0.5   3.3 3.5   5.2  3.6                          10.50-(D)                                                                              --     --     --   --   --   --   --   --                            24.00    4.9    0.2    4.8  0.2   0.0 0.0   0.0  0.0                          ______________________________________                                         -- = not measured                                                        

The AG-EE 388 ZW-level rises rather more rapidly after administration ofthe tablet and reaches its peak somewhat earlier than afteradministration of a capsule. The detection limit of AG-EE 388 ZW isreached after about 6 hours. In accordance with the plasma level curvethe blood sugar-lowering effect sets in rapidly. The glucose levelsreturn to their original level after 6 hours.

In study 3 (open, crossover) a single test subject in a fasting statetook a capsule containing 2 mg or 4 mg of micronised AG-EE 388 ZW or 2mg of AG-EE 623 ZW or a placebo capsule on four different days. The testsubject continued to fast throughout the duration of the experiment.Blood samples were taken at different times. The glucose was measured inwhole blood and the active substance concentration was determined inplasma according to study 1.

Table 4 which follows contains the glucose levels found as a percentagedeviation from the level measured at time 0 and the active substanceconcentrations are shown in ng/ml.

                                      TABLE 4                                     __________________________________________________________________________    (Study 3)                                                                            Glucose                   Active substance concentration               Time after                                                                           [%] deviation against t = 0                                                                             [ng/ml]                                      administration                                                                            2 mg   4 mg   2 mg   2 mg   4 mg   2 mg                           [hours]                                                                              Placebo                                                                            AG-EE 388                                                                            AG-EE 388                                                                            AG-EE 623                                                                            AG-EE 388                                                                            AG-EE 388                                                                            AG-EE 623                      __________________________________________________________________________    0       0     0      0      0    --      0     --                             0.50   -2     0     -3    -10    11      0     --                             0.75    2     0     -1    -14    16     10     --                             1.00   -6    -5     -7    -18    40     72     --                             1.25    0   -12    -15    -29    44     130    0                              1.50   -2   -18    -21    -43    68     150    22                             1.75   -3   -23    -32    -40    82     148    24                             2.00   -2   -29    -38    -33    82     141    7                              2.50   - 2  -27    -34    -33    80     119    0                              3.00    1   -21    -28    -31    72     109    0                              3.50   -4   --     -24    --     59     84     0                              4.00    1   -17    -26    -20    32     71     0                              5.00   -2   -17    -24    -22     0     64     --                             6.00   -5   -16    -23    -28    --     49     0                              7.00   -7   --     -20    -22    --     21     0                              8.00   -10  --     -25    -26    --     18     --                             __________________________________________________________________________     -- = not measured                                                        

Table 4 shows that, as expected, 4 mg of AG-EE 388 ZW lower the bloodglucose more sharply than 2 mg of AG-EE 388 ZW and that the maximumlowering after 4 mg of AG-EE 388 ZW (-38%) and after 2 mg of AG-EE 623ZW (-43%) is virtually identical. However, the effect of 2 mg of AG-EE623 ZW tends to set in more quickly (0.5 Hours) than 4 mg of AG-EE 388ZW (about 1.0 hour) and after 2 mg of AG-EE 623 ZW it reaches themaximum more quickly (1.5 hours) than after 4 mg of AG-EE 388 ZW (2.0h). After the administration of 4 mg of AG-EE 388 ZW or 2 mg of AG-EE623 ZW the blood sugar-lowering effect after reaching the peak slowlydecreases virtually identically until the end of the test period isreached (8 hours). As is shown by a comparison with the placebo data,there still seems to be some blood sugar-lowering effect a 8 hours afteradministration.

A look at the concentration of active substance gives the followingpicture: after the administration of 2 or 4 mg of AG-EE 388 ZW themaximum concentration of active substance is 82 or 150 ng/ml,respectively. The peaks are reached after 1.75 and 1.50 hours,respectively, i.e. rather earlier than the peak reductions in bloodsugar after 2.0 hours. After 4 mg, 18 ng per ml of active substance canstill be detected in the plasma 8 hours after administration. After theadministration of 2 mg of AG-EE 623 ZW the maximum level is unexpectedlylow at 22 to 24 ng/ml; it reaches only about one third of the level (82ng/ml) which is found after the same dose of AG-EE 388 ZW. The level ofactive substance falls below the detection limit extremely quickly.

In order to check the results of study 3, particularly the lowconcentration of active substance and the surprisingly rapid fail in theactive substance concentration (in view of the relatively long durationof effect) after the administration of AG-EE 623 ZW, study 4 was carriedout (not randomised, open, double-blind at each dosage compared withplacebo, group comparison). 6 test subjects in a fasting state weregiven in the morning 0.5 mg, 1.0 or 2.0 mg of AG-EE 623 ZW in the formof a spray-dried tablet or tablets or a placebo tablet or tabletsprepared analogously. 0.25 hours after oral administration a standardbreakfast (B) was eaten, 5.5 hours after administration a standard lunch(L) was eaten and 10 hours after administration a standard evening meal(D) was eaten. Blood samples were taken at different times. The glucoseconcentrations were determined from whole blood according to study 1.The AG-EE 623 ZW concentrations in the plasma were determined by astereospecific competitive enzyme immunoassay (ELISA) with a detectionlimit of 0.5 ng/ml.

The AG-EE 623 ZW-specific ELISA used is based on polyclonal rabbitantibodies directed against AG-EE 623 ZW covalently bound to human serumalbumin. The cross reaction with AG-EE 624 ZW is less than 1:100.Microtitre immunoplates were coated with these antibodies and, afterwashing and blocking of the plates, incubated with standard or unknownplasma samples at 4° C. for one hour with shaking. Then AG-EE 623 ZWcoupled to horse-radish peroxidase was added and incubated for a further4 hours under the same conditions. 1,2-phenylenediamine was used assubstrate for photometrically quantifying the bound enzyme-coupledmolecules.

Table 5 which follows contains the average glucose levels found in thesubject groups as a percentage deviation from the placebo group and theaverage AG-EE 623 ZW concentrations in ng/ml together with the standarddeviations (SD) in the subject groups.

                                      TABLE 5                                     __________________________________________________________________________    (Study 4)                                                                     Time after                                                                             Glucose                 Concentration AG-EE 623 ZW                   admin. of                                                                              [mmol/l]                [ng/ml]                                      AG-EE 623 ZW                                                                           0 mg  0.5 mg                                                                              1 mg  2 mg  0.5 mg                                                                              1 mg  2 mg                             [hours]  mean                                                                             SD mean                                                                             SD mean                                                                             SD mean                                                                             SD mean                                                                             SD mean                                                                             SD mean                                                                             SD                            __________________________________________________________________________    0        4.96                                                                             0.16                                                                             5.21                                                                             0.23                                                                             4.62                                                                             0.06                                                                             4.67                                                                             0.13                                                                             0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                           0.25-(B) 4.82                                                                             0.08                                                                             5.09                                                                             0.22                                                                             4.62                                                                             0.16                                                                             5.14                                                                             0.05                                                                             8.4                                                                              5.4                                                                              14.5                                                                             13.7                                                                             24.1                                                                             19.0                          0.50     4.68                                                                             0.14                                                                             5.01                                                                             0.10                                                                             4.57                                                                             0.12                                                                             4.38                                                                             0.08                                                                             4.7                                                                              8.5                                                                              27.9                                                                             17.9                                                                             50.4                                                                             26.3                          0.75     5.82                                                                             0.24                                                                             5.85                                                                             0.24                                                                             5.36                                                                             0.49                                                                             4.54                                                                             0.22                                                                             1.6                                                                              5.9                                                                              24.2                                                                             10.0                                                                             41.1                                                                             16.1                          1.00     6.31                                                                             0.22                                                                             5.88                                                                             0.32                                                                             4.72                                                                             0.52                                                                             4.27                                                                             0.36                                                                             7.0                                                                              3.8                                                                              15.3                                                                             6.5                                                                              29.9                                                                             11.4                          1.50     4.52                                                                             0.18                                                                             4.05                                                                             0.35                                                                             2.98                                                                             0.32                                                                             2.65                                                                             0.15                                                                             2.6                                                                              2.1                                                                              7.8                                                                              3.5                                                                              13.5                                                                             6.1                           2.00     4.07                                                                             0.15                                                                             3.50                                                                             0.28                                                                             3.20                                                                             0.17                                                                             2.74                                                                             0.24                                                                             1.2                                                                              1.4                                                                              4.7                                                                              2.4                                                                              8.8                                                                              4.4                           3.00     4.36                                                                             0.13                                                                             3.90                                                                             0.16                                                                             3.69                                                                             0.13                                                                             3.07                                                                             0.20                                                                             0.3                                                                              0.6                                                                              1.4                                                                              1.4                                                                              4.3                                                                              3.0                           4.00     4.49                                                                             0.06                                                                             4.08                                                                             0.12                                                                             4.05                                                                             0.13                                                                             3.64                                                                             0.15                                                                             0.0                                                                              0.0                                                                              0.7                                                                              1.0                                                                              1.5                                                                              2.0                           5.00     4.39                                                                             0.12                                                                             4.32                                                                             0.06                                                                             3.94                                                                             0.10                                                                             3.88                                                                             0.15                                                                             0.0                                                                              0.0                                                                              0.3                                                                              0.7                                                                              0.4                                                                              0.9                           5.50-(L) -- -- -- -- -- -- -- -- -- -- -- -- -- --                            6.00     6.74                                                                             0.15                                                                             6.63                                                                             0.27                                                                             6.48                                                                             0.28                                                                             6.47                                                                             0.35                                                                             0.0                                                                              0.0                                                                              0.3                                                                              0.7                                                                              0.2                                                                              0.6                           8.00     5.39                                                                             0.39                                                                             5.61                                                                             0.33                                                                             5.37                                                                             0.21                                                                             4.61                                                                             0.27                                                                             0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                           10.00-(D)                                                                              4.86                                                                             0.20                                                                             4.81                                                                             0.13                                                                             4.57                                                                             0.27                                                                             4.45                                                                             0.21                                                                             0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                           24.00    4.53                                                                             0.10                                                                             4.82                                                                             0.20                                                                             4.69                                                                             0.11                                                                             4.77                                                                             0.06                                                                             0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                           __________________________________________________________________________     -- = not measured                                                        

It is found that the lowering of blood sugar starts after 0.75 hours (2mg) or after 1.0 (1 mg), reaches a peak after 1.5 hours and lasts for upto 2 hours (1 mg) or 5 hours (2 mg) after administration. The maximumlevels of AG-EE 623 are achieved 0.5 hours after administration.Compared with the AG-EE 388 ZW peak levels of 83.5±25.5 ng/ml (see Table3) after the administration of one tablet containing 2 mg of AG-EE 388ZW, the AG-EE 623 ZW maximum level of 50.4±26.3 ng/ml after theadministration of one tablet containing 2 mg of AG-EE 623 ZW issignificantly lower. The AG-EE 623 ZW plasma level is below thedetection limit after only 3.0 hours (1 mg) or 4.0 hours (2 mg) afteradministration. [By comparison, the AG-EE 388 level does not fall belowthe detection limit for 6 hours after administration of a 2 mg tablet(see Table 3)].

Thus, the results of study 4 confirm the surprising findings of study 3;

(a) The AG-EE 623 ZW levels fall more rapidly towards zero than theAG-EE 388 ZW levels, even when the dose is absolutely identical, as canbe seen from the following comparison (Table 6).

(b) In relation to the lowering of blood sugar achieved, substantiallylower plasma levels of AG-EE 623 ZW occur than might have been expectedby halving the dosage of AG-EE 388 ZW.

                                      TABLE 6                                     __________________________________________________________________________                     Maximum                                                          Sub-    Admin.                                                                             concen-                                                                             Concentration                                          Study                                                                             stance                                                                             Dose                                                                             form tration                                                                             [ng/ml]                                                No. AG-EE                                                                              [mg]                                                                             p.o. [ng/ml]                                                                             4     5    6h                                          __________________________________________________________________________    1   388  2  Capsule                                                                            83 ± 18                                                                          16 ± 7                                                                           9 ± 6                                                                           4 ± 4                                    2   388  2  Capsule                                                                            74 ± 15                                                                          17 ± 5                                                                           12 ± 3                                                                          8 ± 4                                    2   388  2  Tablet                                                                             84 ± 25                                                                          19 ± 8                                                                           13 ± 6                                                                          10 ± 6                                   3   388  2  Capsule                                                                            82    32     0   --                                          3   388  4  Capsule                                                                            150   71    64   49                                          3   623  2  Capsule                                                                            24     0    --    0                                          4   623  1  Tablet                                                                             28 ± 18                                                                           0.7 ± 1.0                                                                       0.3 ± 0.7                                                                       0.3 ± 0.7                                4   623  2  Tablet                                                                             50 ± 26                                                                           1.5 ± 2.0                                                                       0.4 ± 0.9                                                                       0.2 ± 0.6                                __________________________________________________________________________

The surprising results of studies 3 and 4 could be explained if theeffective (S)-enantiomer (AG-EE 623 ZW) were eliminated from the bloodunexpectedly much faster than the ineffective (R)-enantiomer (AG-EE 624ZW). Then, when the racemate (AG-EE 388 ZW) is administered, the higherlonger lasting plasma levels could be put down mainly to the ineffective(R)-enantiomer (AG-EE 624 ZW).

In the interests of more precise clarification, study 5 was carried out(randomised, open, crossover). 12 test subjects in a fasting state wereeach given in the morning 1 mg of AG-EE 388 ZW either as a 15 minuteintravenous infusion or by oral route as a drinking solution or orally(micronised) in a capsule. 2 hours after administration a standardbreakfast (B) was eaten, 5 hours after administration a standard lunch(L) was eaten and 10 hours after administration a standard dinner (D)was eaten. Blood samples were taken of different times. The glucoseconcentrations were measured in the plasma as in study 1. The AG-EE 388ZW concentrations were measured in the plasma in accordance with study 1using the non-stereoselective HPLC method and the AG-EE 623 ZWconcentrations were measured in the plasma according to study 4 with theAG-EE 623 ZW-specific ELISA. The plasma concentrations of AG-EE 624 ZWwere calculated as the difference between the two concentrations found:

    C.sub.AG-EE 624 ZW =[C.sub.AG-EE 623 ZW +C.sub.AG-EE 624 ZW ]-C.sub.AG-EE 623 2W

Table 7 which follows contains the average plasma glucose levelsmeasured in mmol/l together with standard deviations (SD), the averageAG-EE 388 ZW concentration measured (388) and the average AG-EE 623 ZWconcentration (623) including standard deviations (SD), as well as theaverage AG-EE 624 ZW concentration (624) calculated in ng/ml.

                                      TABLE 7                                     __________________________________________________________________________    (Study 5)                                                                             Time after                                                                           Glucose                                                                             Concentration [ng/ml]                                            administration                                                                       [mmol/l]                                                                            (388)  (623) (624)-calc.                                 Administration                                                                        [hours]                                                                              mean                                                                             SD mean                                                                              SD mean                                                                             SD mean                                                                             SD                                       __________________________________________________________________________    i.v.    0.00   6.10                                                                             0.66                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                              0.08   6.54                                                                             0.75                                                                             33.3                                                                              12.9                                                                             14.1                                                                             6.6                                                                              19.2                                                                             8.6                                              0.17   6.46                                                                             0.63                                                                             74.8                                                                              18.3                                                                             27.7                                                                             8.2                                                                              47.1                                                                             13.8                                             0.25   6.46                                                                             0.70                                                                             103.8                                                                             23.6                                                                             34.2                                                                             8.5                                                                              69.7                                                                             17.5                                             0.28   6.46                                                                             0.73                                                                             101.8                                                                             15.2                                                                             32.3                                                                             5.3                                                                              69.4                                                                             12.0                                             0.33   6.40                                                                             0.76                                                                             85.6                                                                              15.0                                                                             22.9                                                                             4.6                                                                              62.9                                                                             11.6                                             0.42   6.01                                                                             0.70                                                                             69.6                                                                              13.7                                                                             16.9                                                                             4.3                                                                              52.7                                                                             11.2                                             0.50   5.86                                                                             0.91                                                                             60.1                                                                              13.4                                                                             13.2                                                                             3.2                                                                              46.9                                                                             11.4                                             0.75   5.14                                                                             0.81                                                                             44.2                                                                              13.5                                                                             8.2                                                                              2.9                                                                              36.0                                                                             11.7                                             1.00   4.57                                                                             0.61                                                                             35.8                                                                              10.9                                                                             6.0                                                                              2.7                                                                              29.8                                                                             9.6                                              1.25   4.40                                                                             0.58                                                                             31.4                                                                              10.2                                                                             4.2                                                                              2.1                                                                              27.0                                                                             9.1                                              1.50   4.55                                                                             0.70                                                                             27.0                                                                              9.6                                                                              3.1                                                                              1.7                                                                              23.9                                                                             8.7                                              2.00-(B)                                                                             5.11                                                                             0.57                                                                             21.0                                                                              9.0                                                                              1.5                                                                              1.1                                                                              19.3                                                                             8.3                                              2.50   7.14                                                                             0.79                                                                             17.6                                                                              7.8                                                                              0.8                                                                              1.1                                                                              16.8                                                                             7.3                                              3.00   6.31                                                                             1.79                                                                             13.5                                                                              7.5                                                                              0.6                                                                              1.1                                                                              12.9                                                                             6.9                                              4.00   5.58                                                                             0.93                                                                              9.4                                                                              6.5                                                                              0.2                                                                              0.5                                                                               9.2                                                                             6.2                                              5.00-(L)                                                                             5.48                                                                             0.70                                                                              7.0                                                                              5.7                                                                              0.0                                                                              0.0                                                                               7.0                                                                             5.7                                              6.00   6.53                                                                             1.04                                                                              4.0                                                                              4.8                                                                              0.0                                                                              0.0                                                                               4.0                                                                             4.8                                      i.v.    9.00   6.49                                                                             0.68                                                                              1.5                                                                              2.7                                                                              0.0                                                                              0.0                                                                               1.5                                                                             2.7                                              10.00-(D)                                                                            -- -- --  -- -- -- -- --                                               24.00  6.24                                                                             0.77                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                      p.o.    0.00   5.85                                                                             0.42                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                      solution                                                                              0.25   6.13                                                                             0.52                                                                             16.6                                                                              8.1                                                                              7.8                                                                              4.1                                                                               8.8                                                                             6.8                                              0.50   5.99                                                                             0.48                                                                             35.1                                                                              10.3                                                                             12.4                                                                             3.6                                                                              22.7                                                                             9.1                                              0.75   5.83                                                                             0.48                                                                             40.2                                                                              11.4                                                                             10.0                                                                             3.3                                                                              30.2                                                                             10.3                                             1.00   5.77                                                                             0.35                                                                             39.1                                                                              13.1                                                                             7.8                                                                              5.2                                                                              31.3                                                                             12.4                                             1.50   5.40                                                                             0.30                                                                             30.8                                                                              11.9                                                                             3.4                                                                              2.5                                                                              27.3                                                                             11.0                                             2.00-(B)                                                                             5.11                                                                             0.48                                                                             24.0                                                                              10.7                                                                             2.2                                                                              1.8                                                                              21.8                                                                             10.1                                             3.00   5.40                                                                             1.42                                                                             14.8                                                                              8.6                                                                              0.8                                                                              1.1                                                                              13.9                                                                             8.3                                              4.00   4.86                                                                             0.59                                                                              8.7                                                                              7.5                                                                              0.2                                                                              0.6                                                                               8.4                                                                             7.3                                              5.00-(L)                                                                             5.12                                                                             0.54                                                                              5.6                                                                              5.6                                                                              0.0                                                                              0.0                                                                               5.6                                                                             5.6                                              6.00   5.60                                                                             0.99                                                                              3.5                                                                              4.9                                                                              0.0                                                                              0.0                                                                               3.5                                                                             4.9                                              9.00   5.68                                                                             0.69                                                                              1.8                                                                              2.7                                                                              0.0                                                                              0.0                                                                               1.8                                                                             2.7                                              10.00-(D)                                                                            -- -- --  -- -- -- -- --                                               24.00  5.60                                                                             0.59                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                      p.o. capsule                                                                          0.00   5.32                                                                             0.64                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                              0.25   6.08                                                                             0.60                                                                              1.9                                                                              4.4                                                                              0.7                                                                              1.6                                                                               1.2                                                                             2.8                                              0.50   5.87                                                                             0.67                                                                             23.9                                                                              19.0                                                                             7.3                                                                              7.2                                                                              16.6                                                                             13.1                                             0.75   5.85                                                                             0.64                                                                             34.0                                                                              19.8                                                                             9.7                                                                              5.6                                                                              24.4                                                                             16.1                                             1.00   5.57                                                                             0.62                                                                             35.3                                                                              15.0                                                                             7.9                                                                              3.9                                                                              27.5                                                                             13.5                                             1.50   5.24                                                                             0.44                                                                             31.4                                                                              9.0                                                                              4.3                                                                              2.3                                                                              27.2                                                                             9.1                                              2.00-(B)                                                                             5.04                                                                             0.57                                                                             29.5                                                                              8.0                                                                              3.1                                                                              2.6                                                                              26.2                                                                             7.3                                              3.00   5.04                                                                             1.13                                                                             18.4                                                                              13.2                                                                             1.4                                                                              1.7                                                                              17.0                                                                             11.9                                             4.00   4.43                                                                             0.65                                                                             10.4                                                                              8.5                                                                              0.3                                                                              0.7                                                                              10.1                                                                             8.2                                              5.00-(L)                                                                             4.71                                                                             0.54                                                                              7.0                                                                              6.2                                                                              0.2                                                                              0.4                                                                               6.8                                                                             6.0                                              6.00   5.41                                                                             1.08                                                                              3.4                                                                              5.2                                                                              0.0                                                                              0.0                                                                               3.4                                                                             5.2                                              9.00   5.42                                                                             0.79                                                                              1.4                                                                              2.6                                                                              0.0                                                                              0.0                                                                               1.4                                                                             2.6                                              10.00-(D)                                                                            -- -- --  -- -- -- -- --                                               24.00  5.44                                                                             0.62                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                               0.0                                                                             0.0                                      __________________________________________________________________________     -- = not measured                                                        

The concentrations of active substance from study 5 (Table 7) make itpossible to calculate pharmacokinetic parameters for 0.5 mg of AG-EE 623ZW after oral administration (drinking solution; capsule) in the form of1.0 mg of racemate AG-EE 388 ZW. Table 8 shows the pharmacokineticparameters calculated without a model; it also shows, for comparison,the analogous parameters which can be calculated for AG-EE 623 ZW afteroral administration (tablet) of 0.5 mg of AG-EE 623 ZW from the data ofstudy 4 (Table 5).

                  TABLE 8                                                         ______________________________________                                        Parameter    Study 4    Study 5   Study 5                                     AG-EE 623 ZW (Tablet)   (Solution)                                                                              (Capsule)                                   ______________________________________                                        C.sub.max [ng/ml]                                                                          15.0 ± 8.0                                                                            13.2 ± 3.4                                                                           11.4 ± 5.9                               t.sub.max [hours]                                                                          0.6 ± 0.1                                                                             0.6 ± 0.2                                                                            0.9 ± 0.5                                AUC.sub.0-∞  [ng × h/ml]                                                       14.3 ± 8.6                                                                            16.7 ± 8.5                                                                           16.0 ± 8.1                               t.sub.1/2 λz [hours]                                                                0.5 ± 0.2                                                                             0.9 ± 0.4                                                                            0.8 ± 0.5                                MRT.sub.tot. [hours]                                                                       0.9 ± 0.2                                                                             1.3 ± 0.3                                                                            1.5 ± 0.5                                ______________________________________                                         The parameters denoted:                                                       C.sub.max = maximum plasma concentration                                      t.sub.max = time of maximum plasma concentration                              AUC.sub.0-∞  = area under the curve from 0 to infinity. The             remaining area from the last data point to infinity was calculated by the     loglinear regression line lnC = a + λz × t.                      t.sub. 1/2 λz = terminal halflife, calculated using the loglinear      regression line lnC = a + λz × t of the last data points:        t.sub.1/2 λz = ln2/λz.                                          MRT.sub.tot. = total mean residence time                                 

As ca be seen, the parameters for AG-EE 623 ZW calculated from studies 4and 5 correlate well. This means that the oral administration of AG-EE623 ZW in the form of the racemate AG-EE 388 ZW, i.e. together with thesame amount of AG-EE 624 ZW, has no pharmacokinetic advantages over theoral administration of pure AG-EE 623 ZW.

Moreover, the concentrations of active substance from study 5 (Table 7)make it possible to calculate pharamcokinetic parameters of AG-EE 623 ZWand AG-EE 624 ZW after simultaneously administration in the form of theracemate AG-EE 388 ZW. The parameters calculated without a model areshown in Table 9.

                  TABLE 9                                                         ______________________________________                                        (Study 5)                                                                     Adminis-           (S)-enantiomer                                                                             (R)-enantiomer                                tration                                                                              Parameter   AG-EE 623 ZW AG-EE 624 ZW                                  ______________________________________                                        i.v.   c.sub.max [ng/ml]                                                                         36.3 ± 6.9                                                                              75.4 ± 12.6                                       t.sub.max [hours]                                                                         0.25 ± 0.04                                                                             0.27 ± 0.03                                       AUC.sub.0-∞                                                                         20.8 ± 7.1                                                                              134 ± 58                                          [ng × h/ml]                                                             t.sub.1/2  λz [hours]                                                              0.9 ± 0.8 2.4 ± 1.1                                         MRT.sub.intr. [hours]                                                                     0.9 ± 0.6 3.3 ± 1.7                                         CL [ml/min] 443 ± 140 75 ± 34                                    p.o.   c.sub.max [ng/ml]                                                                         13.2 ± 3.4                                                                              32.3 ± 11.9                                solution                                                                             t.sub.max [hours]                                                                         0.6 ± 0.2 1.0 ± 0.3                                         AUC.sub.0-∞                                                                         16.7 ± 8.5                                                                              111 ± 62                                          [ng × h/ml]                                                             t.sub.1/2  λz [hours]                                                              0.9 ± 0.4 2.3 ± 1.7                                         MRT.sub. tot. [hours]                                                                     1.3 ± 0.3 3.4 ± 2.0                                         f [%]       76 ± 20   83 ± 32                                    ______________________________________                                         The parameters in Table 9 denote:                                             c.sub.max = maximum plasma concentration                                      t.sub.max = time of maximum plasma concentration                              AUC.sub.0-∞  = area under the curve from 0 to infinity                  t.sub.1/2  λz = terminal halflife                                      MRT.sub.intr. = intrinsic mean residence time                                 CL = clearance                                                                MRT.sub.tot. = total man residence time                                       f = absolute (oral) bioavailability                                      

This amazing difference between the two enantiomers is the fact that theeffective enantiomer, AG-EE 623 ZW, in spite of having a relatively longperiod of activity, is surprisingly eliminated more rapidly than theineffective enantiomer, AG-EE 624 ZW, as is additionally demonstrated byFIGS. 1 and 2. After the administration of the racemate, the ineffectiveenantiomer, AG-EE 624 ZW, is therefore present not only as anunnecessary additive in plasma concentrations which are just as high asthose of the effective enantiomer. AG-EE 623 ZW, but is present inunexpectedly higher maximum and long-lasting levels. The effect of this,as shown in Table 6, e.g. on administration of one tablet containing 2mg of AG-EE 388 ZW or one tablet containing 1 mg of AG-EE 623 ZW, isthat the maximum concentrations are 84±25 and 28±18 ng/ml, respectively,and the concentrations after 4 hours are 19±8 and 0.7±1.0 ng/ml,respectively, after 5 hours 13±6 and 0.3±0.7 ng/ml, respectively, andafter 6 hours 10±6 and 0.3±0.7 ng/ml, respectively.

Thus, compared with the administration of AG-EE 388 ZW, the surprisingadvantage of the administration of AG-EE 623 ZW is that unnecessarilyhigh and long-lasting levels of the substance in the body are avoided,which is of major importance in long-term therapy such as that ofdiabetes mellitus.

The studies described above show that the new (S)-enantiomer, namely(S)(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoicacid, as a vehicle of blood sugar-lowering activity, is far superior toAG-EE 388 ZW, because of this surprisingly rapid elimination from theblood which was not foreseeable in view of its relatively long durationof activity, and these superior qualities go far beyond the "normal"advantage of an enantiomer over its racemate, namely the advantage ofhalving the dose.

The present invention therefore relates to the new(S)(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]-benzoicacid or an(S)(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]-benzoicacid, which is substantially optically pure, e.g. having an opticalpurity of at least ee=95%, preferably 98 to 100%, the physiologicallyacceptable salts thereof with inorganic or organic acids or bases,pharamceutical compositions containing this compound or thephysiologically acceptable salts thereof and processes for preparingthem.

According to the invention, the new compound is obtained by thefollowing methods:

a) reaction of the (S)-amine of formula ##STR21## with a carboxylic acidof general formula ##STR22## wherein

W represents a carboxy group or a carboxy group protected by aprotecting group, or with the reactive derivatives thereof optionallyprepared in the reaction mixture and, if necessary, subsequent cleavingof a protecting group.

Reactive derivatives of a compound of general formula II may be, forexample, the esters thereof such as the methyl, ethyl or benzyl ester,the thioesters thereof such as the methylthio or ethylthioesters, thehalides thereof such as acid chloride, the anhydrides or imidazolidesthereof.

The reaction is conveniently carried out in a solvent such as methylenechloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionallyin the presence of an acid-activating agent or a dehydrating agent, e.g.in the presence of ethylchloroformate, isobutylchloroformate,thionylchloride, phosphorus trichloride, phosphorus pentoxide,N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, or an agent which activates theamino group, e.g. phosphorus trichloride, and optionally in the presenceof an inorganic base such as sodium carbonate or a tertiary organic basesuch as triethylamine or pyridine which may simultaneously serve assolvent, at temperatures between -25° and 250° C., but preferably attemperatures between -10° C. and the boiling temperature of the solventused. The reaction may also be carried out without a solvent andmoreover any water formed during the reaction may be removed byazeotropic distillation, e.g. by heating with toluene using a waterseparator, or by the addition of a drying agent such as magnesiumsulphate or molecular sieve.

If necessary, the subsequent cleaving of a protecting group ispreferably carried out by hydrolysis, conveniently either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric,trifluoroacetic or trichloroacetic acid or in the presence of a basesuch as sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxane at temperatures between -10° and 120°C., e.g. at temperatures between ambient temperature and the boilingtemperature of the reaction mixture.

A tert.-butyl group used as protective group may also be cleavedthermally, optionally in an inert solvent such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial aceticacid and preferably in the presence of a strong acid such astrifluoroacetic, hydrobromic, p-toluenesulphonic, sulphuric, phosphoricor polyphosphoric acid.

Moreover, a benzyl group used as protective group may also be cleavedhydrogenolytically in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide.

b) Cleaving an (S)-compound of general formula ##STR23## wherein

A represents a group which may be converted into a carboxy group byhydrolysis, thermolysis or hydrogenolysis.

Examples of hydrolysable groups include functional derivatives of thecarboxy group such as the unsubstituted or substituted amides, esters,thioesters, orthoesters, iminoethers, amidines or anhydrides thereof, anitrile group, a tetrazolyl group, an optionally substituted1,3-oxazol-2-yl or 1,3-oxazolin-2-yl group and examples ofthermolytically cleavable groups include the esters with tertiaryalcohols, e.g. a tert.butylester, and examples of hydrogenolyticallycleavable groups include the aralkyl groups, e.g. a benzyl group.

The hydrolysis is conveniently carried out either in the presence of anacid such as hydrochloric, sulphuric, phosphoric, trifluoroacetic ortrichloroacetic acid or in the presence of a base such as sodiumhydroxide or potassium hydroxide in a suitable solvent such as water,water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxane at temperatures between -10° and 120° C., e.g. attemperatures between ambient temperature and the boiling temperature ofthe reaction mixture.

If A in a compound of general formula III represents a nitrile oraminocarbonyl group, these groups may be converted into the carboxygroup by means of 100% phosphoric acid at temperatures between 100° and180° C., preferably at temperatures between 120° and 160° C., or using anitrite, e.g. sodium nitrite, in the presence of an acid such assulphuric acid, whilst the latter may conveniently be used as solvent atthe same time, at temperatures between 0° and 50° C.

If A in a compound of general formula III represents atert.butyloxycarbonyl group, for example, the tert.butyl group may alsobe cleaved thermally, optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane orglacial acetic acid and preferably in the presence of a strong acid suchas trifluoroacetic acid, hydrobromic acid, p-toluenesulphonic acid,sulphuric acid, phosphoric acid or polyphosphoric acid, at temperaturesbetween 0° and 100° C., preferably at temperatures between 20° C. andthe boiling temperature of the solvent used.

If A in a compound of general formula III represents a benzyloxycarbonylgroup, for example, the benzyl group may also be cleavedhydrogenolytically in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,methanol/water, ethanol/water, glacial acetic acid, ethyl acetate,dioxane or dimethylformamide, preferably at temperatures between 0° and50° C., e.g. at ambient temperature and under a hydrogen pressure offrom 1 to 5 bar.

c) Reaction of an (S)-compound of general formula ##STR24## wherein

W' represents a carboxy group or an alkoxycarbonyl group having a totalof 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group maybe substituted by a phenyl group, with a compound of general formula

    Z--CH.sub.2 --CH.sub.3                                     (V)

wherein

Z represents a nucleophilically exchangeable group such as a halogenatom, a sulphonyloxy group or, together with the adjacent hydrogen atom,represents a diazo group, optionally followed by hydrolysis orhydrogenolysis.

The reaction is conveniently carried out with a corresponding halide,sulphonic acid ester or sulphuric acid diester, e.g. with ethyl bromide,ethyl iodide, diethylsulphate, ethyl p-toluenesulphonate orethylmethanesulphonate, or with diazoethane, optionally in the presenceof a base such as sodium hydride, potassium carbonate, sodium hydroxide,potassium tert.butoxide or triethylamine, preferably in a suitablesolvent such as acetone, diethylether, tetrahydrofuran, dioxane,pyridine or dimethylformamide at temperatures between 0° and 100° C.,preferably at temperatures between 20° and 50° C.

If W' in a compound of general formula IV represents a carboxy group,this can be converted into the corresponding ester compound.

If necessary, the subsequent hydrolysis is carried out either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric,trifluoroacetic or trichloroacetic acid or in the presence of a basesuch as sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxane at temperatures between -10° and 120°C., e.g. at temperatures between ambient temperature and the boilingtemperature of the reaction mixture, or the subsequent hydrogenolysis iscarried out in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide under a hydrogen pressure of from 1 to 10 bar.

d) Enantioselective reduction of a compound of general formula ##STR25##wherein

W' represents a carboxy group or an alkoxycarbonyl group having a totalof 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group maybe substituted by a phenyl group, and

Y represents a group of the formula ##STR26## and optional subsequenthydrolysis.

The reduction is preferably carried out with hydrogen in the presence ofa suitable chiral hydrogenation catalyst in a suitable solvent such asmethanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran,methanol/tetrahydrofuran, methanol/methylene chloride, ethanol/methylenechloride of isopropanol/methylene chloride at temperatures between 0°and 100° C., but preferably at temperatures between 20° and 50° C.,under a hydrogen pressure of between 1 and 1000 bar, preferably between5 and 100 bar, and conveniently with the addition of 0.1 to 5%,preferably 0.3 to 1%, of titanium(IV)tetraisopropoxide, preferably withthe exclusion of oxygen from the air. The reduction is preferablycarried out with the (Z)-form of a compound of general formula VI.

Examples of chiral hydrogenation catalysts are the corresponding metalligand complexes such as Ru(OCO-CH₃)₂ [(S)-BINAP], Ru₂ Cl₄ [(S)-BINAP]₂×N(C₂ H₅)₃, Rh[(S)-BINAP-NBD]ClO₄ or Rh[(-)-NORPHOS-COD]BF₄.

During the catalytic hydrogenation, a benzyloxycarbonyl group maysimultaneously be reduced and converted into the carboxy group.

If necessary, the subsequent hydrolysis is carried out either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric,trifluoroacetic or trichloroacetic acid or in the presence of a basesuch as sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxane at temperatures between -10° and 120°C., e.g. at temperatures between ambient temperature and the boilingtemperature of the reaction mixture.

e) Oxidation of an (S)-compound of general formula ##STR27## wherein

W" represents a group which may be converted into a carboxy group byoxidation.

An example of an oxidisable group of this kind might be a formyl groupand the acetals thereof, a hydroxymethyl group and the ethers thereof,an unsubstituted or substituted acyl group such as acetyl, chloroacetyl,propionyl, malonic acid-(1)-yl group or a malonic ester-(1)-yl group.

The reaction is carried out with an oxidising agent in a suitablesolvent such as water, glacial acetic acid, methylene chloride, dioxaneor glycoldimethylether at temperatures between 0° and 100° C., butexpediently at temperatures between 20° C. and 50° C. However, thereaction is preferably carried out with silver oxide/sodium hydroxidesolution, manganese dioxide/acetone or methylene chloride, hydrogenperoxide/sodium hydroxide solution, bromine or chlorine/sodium orpotassium hydroxide solution, chromium trioxide/pyridine or pyridiniumchlorochromate.

f) Separation of a mixture, consisting of any desired amount of the(S)-enantiomer of general formula ##STR28## and any desired amount ofthe (R)-enantiomer of general formula ##STR29## wherein

W' represents a carboxy group or an alkoxycarbonyl group having a totalof 2 to 5 carbon atoms, wherein the alkyl moiety of the alkoxy group maybe substituted by a phenyl group, preferably a 50/50 mixture, via thediastereomeric adducts, complexes or salts thereof, and followed ifnecessary by hydrolysis or hydrogenolysis.

The separation is preferably carried out using column or HPLchromatography by forming the diastereomeric adducts or complexes on achiral phase.

If necessary, the subsequent hydrolysis is carried out either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric,trifluoroacetic or trichloroacetic acid or in the presence of a basesuch as sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, methanol, methanol/water, ethanol, ethanol/water,water/isopropanol or water/dioxane at temperatures between -10° and 120°C., e.g. at temperatures between ambient temperature and the boilingtemperature of the reaction mixture, or the subsequent hydrogenolysis iscarried out in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide under a hydrogen pressure of from 1 to 10 bar.

The (S)-enantiomer thus obtained according to the invention, having anoptical purity of, preferably, at least 90% can be converted byfractional crystallisation into an (S)-enantiomer having an opticalpurity of at least 95% , preferably 98 to 100%.

The same applies to the (S)-compounds according to the invention offormulae III, IV and VII, and more particularly the esters thereof.

The (S)-enantiomer thus obtained according to the invention can beconverted into the salts thereof, more particularly, for pharmaceuticaluse, into the physiologically acceptable salts thereof with inorganic ororganic acids or bases. Examples of such acids include hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, lactic acid,citric acid, tartaric acid, succinic acid, maleic acid or fumaric acidand examples of bases include sodium hydroxide, potassium hydroxide,calcium hydroxide, cyclohexylamine, ethanolamine, diethanolamine,triethanolamine, ethylenediamine or lysine.

The compounds of formulae I to IX used as starting materials are knownfrom the literature in some cases or may be obtained by methods knownper se.

The (S)-amine of formula I can be obtained from the correspondingracemic amine by racemate cleaving, e.g. by means of fractionalcrystallisation of the diastereomeric salts with suitable opticallyactive acids, preferably with N-acetyl-L-glutamic acid, and if necessaryrecrystallisation and subsequent decomposition of the salts, by columnor HPL-chromatography on chiral phases, optionally in the form of anacyl derivative, or by forming diastereomeric compounds, then separatingand subsequently cleaving them.

Moreover, the (S)-amine of formula I may be prepared by enantioselectivereduction using hydrogen in the presence of a suitable chiralhydrogenation catalyst, starting from a corresponding N-acyl-ketimine orenamide, conveniently with the addition of 0.1 to 5% titaniumtetraisopropoxide, optionally with subsequent cleaving of the acyl groupsuch as the formyl or acetyl group, by diastereoselective reduction of acorresponding ketimine or hydrazine chirally substituted at the nitrogenatom, using hydrogen in the presence of a suitable hydrogenationcatalyst, expediently with the addition of 0.1 to 5% titaniumtetraisopropoxide, and optionally followed by cleaving of the chiralauxiliary group e.g. the (S)-1-phenethyl group, by catalytichydrogenolysis, or by diastereoselective addition of a correspondingorganometallic compound, preferably a Grignard or lithium compound, to acorresponding aldimine chirally substituted at the nitrogen atom,optionally with the addition of 0.1 to 10% titanium tetraisopropoxide,subsequent hydrolysis and optional separation of the resultingdiastereomers and subsequent cleaving of the chiral auxiliary group,e.g. the (R)-1-phenethyl group by catalytic hydrogenolysis, and ifnecessary the (S)-amine may be obtained in a higher enantiomeric purityby salt formation with suitable optically active acids, preferably withN-acetyl-L-glutamic acid, and if necessary single or multiplerecrystallisation and subsequent decomposition of the salt.

The compounds of general formulae III, IV and VII used as startingmaterials are obtained by reacting the (S)-amine I with a correspondingcarboxylic acid or a reactive derivative thereof and optionallysubsequently splitting off any protecting group used.

The compound of general formula VI used as starting material is obtainedby acylating the corresponding imino compound or the organometalliccomplexes thereof with the corresponding carboxylic acid or with thereactive derivatives thereof with optional subsequent cleaving of anester group.

The new (S)-enantiomer is virtually non-toxic; for example, after asingle administration of 1000 mg/kg p.o. (suspension in 1%methylcellulose) to 5 male and 5 female rats, no animals died within theobservation period of 14 days.

In view of its pharmacological and pharmacokinetic properties, the(S)-enantiomer prepared according to the invention (AG-EE 623 ZW) andthe physiologically acceptable salts thereof are suitable for thetreatment of diabetes mellitus. For this purpose, AG-EE 623 ZW or thephysiologically acceptable salts thereof, optionally combined with otheractive substances, may be incorporated in the conventional galenicpreparations such as plain or coated tablets, capsules, powders,suppositories, suspension or injectable solutions. The single dose foradults is 0.1 to 20 mg, preferably 0.25 to 5 mg, especially 0.25, 0.5,1.0, 1.5, 2.0, 2.5, 3.0 or 5.0 mg, once, twice or three times a day.

The present invention further relates to the new (S)-amine of formula Iwhich is a valuable intermediate product for preparing the new(S)-enantiomer, and the addition salts thereof with inorganic or organicacids.

The present invention also relates to the new compounds of generalformulae III, IV and VII which are valuable intermediate products forpreparing the new (S)-enantiomer, and the addition salts thereof withinorganic or organic acids.

The Examples which follow are intended to illustrate the invention:

EXAMPLE A (S)-1-(2-Piperidino-phenyl)-3-methyl-1-butylamine

A stirred solution of 122 g (0.495 mol) of racemic1-(2-piperidino-phenyl)-3-methyl-1-butylamine in 1000 ml of acetone ismixed with 93.7 g (0.495 mol) of N-acetyl-1-glutaminic acid. The mixtureis refluxed over a vapour bath and methanol is added in batches (a totalof about 80 ml) until a clear solution is obtained. After this has beenleft to cool and stand overnight at ambient temperature, the crystalsobtained are removed by suction filtering, washed twice with 200 ml ofcold acetone at -15° C. and then dried. The product obtained [98.9 g;melting point: 163°-166° C.; [α]_(D) ³⁰ =+0.286°(c=1 in methanol)] isrecrystallised from 1000 ml of acetone with the addition of 200 ml ofmethanol, thereby obtaining the(S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine as the addition saltof N-acetyl-L-glutaminic acid.

Yield: 65.1 g (60.4% of theory),

Melting point: 168°-171° C.

Calculated: C 63.42; H 8.56; N 9.65. Found: C 63.64; H 8.86; N 9.60.

[α]_(D) ²⁰ =+0.357° (c=1 in methanol)

The free amine is obtained as an oil by liberation, for example, with asodium hydroxide or ammonia solution, extraction with toluene, ether,ethylacetate or methylene chloride, for example, and drying, filteringand evaporation of the extract in vacuo.

The (S)-configuration of the amine was demonstrated as follows:

Reaction of the amine with (S')-1-phenethylisocyanate in ether to obtainthe corresponding urea derivative [melting point: 183°-184° C.; [α]_(D)²⁰ =-2.25° (c=1 in methanol)], growing crystals from ethanol/water (8/1)and subsequent X-ray structural analysis showed the (S,S')-configurationfor the urea derivative and consequently the (S)-configuration for theamine used.

Enantiomeric purity was determined as follows:

1. Acetylation of a sample of the amine with 1.3 equivalents of aceticanhydride in glacial acetic acid at 20° C. overnight.

2. Investigation of the N-acetyol derivative (melting point: 128°-132°C.) by HPLC on a chiral phase HPLC column made by Baker, in which(S)-N-(3,5-dinitrobenzoyl)-2-phenyl-glycine is covalently bonded toaminopropyl silica gel (particle size 5 μm, spherical, pore size 60 A;column length: 250 mm with internal diameter 4.6 mm; eluant:n-hexane/isopropanol (100/5); flow rate: 2 ml/minute; temperature: 20°C.; UV-detection at 254 nm.) Found: peak 1(R): peak 2(S)=0.75%: 99.25%,

ee (enantiomeric excess)=98.5% (S).

The (S)-amine may be converted into the dihydrochloride hydrate thereofusing ethereal hydrogen chloride solution.

Melting point: 135°-145° C. (decomposition) Calc. (x H₂ O): C 56.99; H8.97; N 8.31; Cl 21.02. Found: C 56.85; H 8.93; N 8.38; Cl 21.25.

[α]_(D) ²⁰ =+26.1° (c=1 in methanol)

EXAMPLE BN-Acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine

At ambient temperature, 4.7 ml (81.8 mMol) of glacial acetic acid, 25.7g (98.2 mMol) of triphenylphosphine, 34.2 ml (245 mMol) of triethylamineand 7.0 ml (81.8 mMol) of carbon tetrachloride re added to a solution of20 g (81.8 mMol) of freshly preparedisobutyl-(2-piperidino-phenyl)-ketimine in 200 ml of acetonitrile andthe resulting mixture is stirred for 18 hours at ambient temperature. Itis then evaporated down in vacuo and distributed between ethyl acetateand water. The organic extract is dried and filtered and evaporated downin vacuo. The evaporation residue is purified by column chromatographyon silica gel (toluene/ethyl acetate=10/1), eluting first the (E)-formand then the (Z)-form.

(E)-form

Yield: 6.1 g (26% of theory),

Melting point: 135°-137° C. (ethylacetate/petroleum ether)

Calculated: C 75.48; H 9.15; N 9.78. Found: C 75.47; H 9.35; N 9.70.

(Z)-form

Yield: 3.1 g (13% of theory),

Melting point: 140°-143° C. (ethylacetate)

Calculated: C 75.48; H 9.15; N 9.78. Found: C 75.56; H 9.30; N 9.79.

EXAMPLE CN-Acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine

17 ml (0.18 mol) of acetic anhydride are added dropwise, at an internaltemperature of 0° C., to a stirred solution of 44 g (0.18 mol) offreshly prepared isobutyl-(2-piperidino-phenyl)-ketimine in 440 ml oftoluene. The mixture is stirred for a further 3 hours at 0° C. and for15 hours at ambient temperature, then evaporated down in vacuo, theevaporation residue is dissolved in ethyl acetate and extracted severaltimes with aqueous sodium hydrogen carbonate solution. The organic phaseis dried, filtered and evaporated down in vacuo. The evaporation residueis purified by column chromatography on silica gel (toluene/ethylacetate=5/1), eluting first the (E)-form and then the (Z)-form.

(E)-form

Yield: 3.0 g (5.8% of theory),

(Z)-form

Yield: 17.8 g (34.5% of theory),

Melting point: 139°-141° C. (ethyl acetate)

Calculated: C 75.49; H 9.15; N 9.78. Found: C 75.68; H 8.99; N 9.86.

EXAMPLE DN-Acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine

0.57 g (1.99 mMol) of(Z)-N-acetyl-N-[1-(2-piperidinophenyl)-3-methyl-1-buten-1-yl]-amine,melting point 139°-141° C., are dissolved in 10 ml of degassed solventmixture (methanol/methylene chloride=5/1) under an Argon atmosphere andadded to a solution of 16.8 mg (1 mol %) of the NOYORI-catalystRu(O-acetyl)₂ [(S)-BINAP](prepared from [Ru(COD)Cl₂ ]_(n) with (S)-BINAP[=(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], triethylamine andsodium acetate), and 3.4 mg (0.5 mol %) of titanium tetraisopropoxide in10 ml of degassed solvent mixture (methanol/methylene chloride=5/1). Thereaction mixture is drawn into an autoclave which is evacuated at 10⁼²mbar. It is rinsed several times with hydrogen at 4 bar and the mixtureis then hydrogenated at 10° C. under 100 bar until the hydrogen uptakehas ceased (170 hours). Then the reddish-brown solution is evaporateddown in vacuo, the evaporation residue is refluxed with 30 ml ofn-hexane and filtered hot to remove any insoluble matter. When thefiltrate cools, crystallisation occurs.

Yield: 0.31 g (54% of theory),

Melting point: 127°-131° C.

enantiomeric purity: ee=82% (S) [HPLC method: see Example A].

14% of the racemic N-acetyl-amine of melting point 154°-156° C. can beobtained from the insoluble matter obtained when boiling with 30 ml ofn-hexane, by further decoction with n-hexane, filtration andcrystallisation from the hexane solution.

EXAMPLE E (S)-1-(2-Piperidino-phenyl)-3-methyl-1-butylamine

1 g (3.47 mMol) ofN-acetyl-N-[(S)-1-(2-piperidinophenyl]-3-methyl-1-butyl]-amine (meltingpoint: 128°-133° C.; ee=99.4%] are refluxed in 10 ml of concentratedhydrochloric acid for 5.5 hours, then cooled and poured into a mixtureof concentrated ammonia and ice. The mixture is extracted twice withethyl acetate, the organic phase is washed with water, dried andfiltered and then evaporated down in vacuo. Yield: 0.84 g (98.8% oftheory) oil amine.

By re-acetylation with 0.42 ml (1.3 equivalents) of acetic anhydride in8.4 ml of glacial acetic acid overnight at ambient temperature,evaporation in vacuo, distribution of the evaporation residue betweenethyl acetate and saturated aqueous sodium bicarbonate solution thendrying, filtering and evaporation of the organic extract in vacuo, 0.83g (84.7% of theory) ofN-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine areobtained (melting point: 130°-132° C.;

EXAMPLE F Ethyl2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl]-benzoate

Prepared from isobutyl-(2-piperidino-phenyl)-ketimine and3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example B.Purification by column chromatography on silicagel(toluene/acetone=10/1), eluting first the (E)-form and then the(Z)-form.

(E)-form

Yield: 4% of theory,

Melting point: 101°-103° C.

Calculated: C 72.77; H 8.00; N 5.85. Found: C 72.74; H 7.78; N 5.86.

(Z)-form

Yield: 28.1% of theory,

Melting point: 124°-127° C. (petroleum ether/toluene=5/1) Calculated: C72.77; H 8.00; N 5.85. Found: C 72.90; H 7.86; N 5.83.

EXAMPLE GN-[(S')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine

17 g (49 mMol) ofN-[(S')-1-phenethyl]-isobutyl-(2-piperidinophenyl)-ketimine, boilingpoint 150°-155° C./0.3 torr [prepared fromisobutyl-(2-piperidinophenyl)-ketone and (S')-1-phenethyl-amine (made byFluka, ee=99.6%) in toluene+triethylamine by dropwise addition of asolution of titanium tetrachloride in toluene] are dissolved in 170 mlof anhydrous ethanol. 1.7 g of titanium tetraisopropoxide and 8 g ofRaney nickel are added and the mixture is hydrogenated at 50° C. under200 bar of hydrogen. After 20 hours a further 8 g of Raney nickel areadded and the mixture is hydrogenated for a further 52 hours under thesame conditions. The catalyst is filtered off over a layer of Celite ona G3-mess and the filtrate is evaporated down in vacuo.

Yield: 13.1 g (76.6% of theory),

Boiling point: 152° C./0.2 torr

Calculated: C 82.23; H 9.78; N 7.99. Found: C 82.00; H 10.03; N 7.74.

[α]_(D) ²⁰ =-55.3° (c=1.1 in methanol)

The diastereomeric purity is determined by HPLC on a Lichrosorb RP18HPLC column made by E. Merck (Germany); column length: 250 mm with aninternal diameter of 4 mm; particle size: 7 μm. Eluant:methanol/dioxane/0.1% aqueous sodium acetate solution, adjusted to pH4.05 with acetic acid (135/60/5); temperature: 23° C.; UV-detection at254 nm.

Found: peak 1(S,S'): peak 2(R,S')=98.4%: 1.4%, de (diastereomericexcess)=97.0% (S,S').

EXAMPLE H (S)-1-(2-Piperidino-phenyl)-3-methyl-1-butylamine

12.5 g (36 mMol) ofN-[(S')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-aminewith a de of 97.0% (S,S') are dissolved in 125 ml of water and 3.6 ml ofconc. hydrochloric acid. 1.3 g of (10%) palladium/charcoal are added andthe mixture is hydrogenated at 50° C. under 5 bar of hydrogen. After thehydrogen uptake has ended (10 hours) the mixture is filtered over alayer of Celite to remove the catalyst.

The filtrate is made alkaline with conc. ammonia with the addition ofice and extracted with ethyl acetate. The organic extract is dried andfiltered and evaporated down in vacuo.

Yield: 6.4 g (72.1% of theory),

Boiling point: 115°-117° C./0.4 torr

Enantiomeric purity: ee=93.5% (S) [HPLC method (after previousacetylation): see Example A].

EXAMPLE IN-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine

A solution of 2 g (6.84 mMol) ofN-[(R')-1-phenethyl]-(2-piperidino-benzaldimine) [prepared fromequimolar amounts of 2-piperidino-benzaldehyde and (R')-1-phenethylamineby standing overnight at ambient temperature and subsequent drying withsodium sulphate in ether solution] in 20 ml of anhydrous tetrahydrofuranis added dropwise to a solution of 27.4 mMol (4 equivalents) ofisobutyl-magnesium bromide in 22 ml of anhydrous tetrahydrofuran, whichis stirred in a bath at 60° C. After 18 hours the bath temperature isincreased to 80° C. and a further 2 equivalents of isobutyl-magnesiumbromide in 11 ml of tetrahydrofuran are added. After 12 hours stirringat 80° C. 2 equivalents of isobutyl-magnesium bromide solution are addedonce again. After about 90 hours at 80° C. the mixture is cooled, excessconc. hydrochloric acid is added and the resulting mixture is evaporatedto dryness in a water jet vacuum. The evaporation residue is dissolvedin water and made alkaline with conc. ammonia. It is extracted withether, the organic extract is dried over sodium sulphate, filtered andevaporated in vacuo. The evaporation residue is purified by columnchromatography on silica gel (toluene/acetone=95/5).

Yield: 0.20 g (8.3% of theory),

Melting point: <20° C.

The diastereomeric purity is determined by HPLC as in Example G.

Found: peak 1(R,R'): peak 2(S,R')=4.4%:95.6%, de (diastereomericexcess)=91.2% (S,R').

In an analogous mixture with 2.0 g of the Schiff's base and a total of 6equivalents of isobutyl-magnesium bromide in toluene/tetrahydrofuran(4/1) and with the addition of 5% titanium(IV)-tetraisopropoxide andheating for 60 hours at 100° C. in a glass tank, a yield of 5% wasachieved with a de of 97.6% (S,R').

EXAMPLE K (S)-1-(2-Piperidino-phenyl)-3-methyl-1-butylamine

A solution of 0.15 g (0.428 mMol) ofN-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amide(de=91.2%), 0.47 ml (0.47 mMol) of 1N-hydrochloric acid and 1.5 ml ofwater is hydrogenated in the presence of 20 mg of 10% palladium/charcoalfor 5 hours at 50° C. under 3.4 bar of hydrogen. The mixture is filteredover kieselguhr, made alkaline with conc. ammonia and extracted withethyl acetate. The extract is dried, filtered and evaporated in vacuo.

Yield: 0.066 g (62.8% of theory),

Melting point: <20° C.

Enantiomeric purity: ee=87.6% (S) [HPLC method (after previousacetylation): see Example A].

EXAMPLE 1 Ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

0.48 g (1.91 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 0.60 g(2.29 mMol) of triphenylphosphine, 0.80 ml (5.73 mMol) of triethylamineand 0.18 ml (1.91 mMol) of carbon tetrachloride are added successivelyto a solution of 0.47 g (1.91 mMol) of(S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 5 ml ofanhydrous acetonitrile and the resulting mixture is stirred for 20 hoursat ambient temperature. It is then evaporated down in vacuo anddistributed between ethyl acetate and water. The organic extract isdried and filtered and evaporated down in vauco. The evaporation residueis purified by column chromatography on silica gel (toluene/ethylacetate=10/1).

Yield: 0.71 g (77.3% of theory),

Melting point: 110°-112° C.

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.29; H 8.42; N 5.80.

The enantiomeric purity is determined by HPLC on a chiral phase HPLCcolumn made by Baker, in which (S)-N-3,5-dinitrobenzoyl-leucine iscovalently bound to aminopropyl silica gel (particle size: 5 μm,spherical, 60 A pore size; column length; 250 mm with an internaldiameter of 4.6 mm; eluant: n-hexane/tetrahydrofuran/methylenechloride/ethanol (90/10/1/1); flow rate: 2 ml per minute; temperature:20° C.; UV detection at 242 nm).

Found: peak 1(R): peak 2(S)=0.75%: 99.25%, ee=98.5% (S).

EXAMPLE 2 Ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid are addedat ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous(S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml ofabsolute toluene and the mixture is stirred until dissolved. Then 2.38 g(11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixtureis stirred at ambient temperature. After 24 hours a further 0.54 g (2.14mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture isstirred overnight. It is then cooled to an internal temperature of +5°C. and suction filtered to separate the precipitate, which is washedonce with 5 ml of toluene. The combined toluene filtrates are evaporateddown in vacuo to a volume of about 10 ml. The resulting solution isheated over the stem bath and petroleum ether is added in batchesthereto (total of 55 ml) until the turbidity remains. It is cooled inice, whereupon crystallisation takes place. It is suction filtered anddried at 75° C/4 torr. The product obtained (4.57 g; melting point111°-112° C; ee=98.9%) is suspended in 50 ml of petroleum ether. Themixture is heated over the steam bath and sufficient toluene is added inbatches (8 ml in total) until a solution is obtained. This is thencooled in ice and suction filtered to separate the crystals, which aredried at 75° C./4 torr.

Yield: 3.93 g (74.3% of theory),

Melting point: 117°-118° C.

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.44; H 8.43; N 5.93.

[α]_(D) ²⁰ =+9.4° (c=1.01 in methanol) Enantiomeric purity: ee=99.9%[HPLC method: see Example 1[

EXAMPLE 3(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid

A solution of 3.79 g (7.88 mMol) of ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)aminocarbonylmethyl]-benzoate(ee =99.9%) in 37 ml of ethanol is stirred in a bath at 60° C. and 10 ml(10 mMol) of 1N sodium hydroxide solution are added. After 4 hoursstirring at 60° C., 10 ml (10 mMol) of 1-N-hydrochloric acid are addedin the warm and the mixture is left to cool to ambient temperature.After inoculation and standing overnight, the mixture is cooled for afurther hour in ice, with stirring. The crystals are separated bysuction filtering and washed twice with 5 ml of water. They are thendried at 75° C. up to a final temperature of 100° C./4 torr in a vacuumdrying cupboard over phosphorus pentoxide.

Yield: 3.13 g (87.7% of theory),

Melting point: 130°-131° C. (high-melting form)

Calculated: C 71.64; H 8.02; N 6.19. Found: C 71.48; H 7.87; N 6.39.

[α]_(D) ²⁰ =+7.45° (c=1.06 in methanol)

The enantiomeric purity is determined by HPLC on a chiral phase HPLCcolumn made by ChromTech (Sweden) with an AGP(α1-acid glycoprotein)phase; internal diameter: 4.0 mm; length: 100 mm; particle diameter: 5μm. Temperature: 20° C.; eluant: 0.1% aqueous KH₂ PO₄ solution (=A)+20%acetonitrile (=B), gradient increase within 4 minutes to 40% (B); flowrate: 1 ml per minute; UV detection at 240 nm. Retention time(S)-enantiomer: 2.7 minutes; retention time (R)-enantiomer: 4.1 minutes.

Found: (S):(R)=99.85%: 0.15%, ee=99.7% (S).

When a sample is recrystallised from ethanol/water (2/1) the meltingpoint does not change. When a sample is heated in petroleumether/toluene (5/3) the undissolved portion is filtered (melting point:130°-131° C.) and the filtrate is rapidly cooled, the low melting formof the title compound is obtained, melting point 99°-101° C.

Calculated: C 71.64; H 8.02; N 6.19. Found: C 71.66; H 7.97; N 6.44.

The low melting form and the high melting form differ in their infra-redKBr spectra but not in their infra-red solution spectra (methylenechloride).

If a sample of the low melting form is heated beyond its melting point asecond melting point is observed at 127°-130° C.

If a sample of the low-melting form is recrystallised from ethanol/water(2/1), the high melting form is obtained.

The high melting form and the low melting form were investigated byDifferential Scanning Calorimetry (DSC) [Mettler apparatus, TA-300system; measuring cell; DSC 20; made by Mettler, CH-8306 Greifensee,Switzerland] with the following results:

    ______________________________________                                        Compound of                                                                   Example 3                                                                              Heating rate 10° K./min.                                                               Heating rate 3° K./min.                       ______________________________________                                        High melting                                                                           Uniform melting peak                                                                          Uniform melting peak                                 form     with melting tempera-                                                                         with melting tempera-                                         ture of 133° C.;                                                                       of 132° C.;                                            melting enthalpy:                                                                             melting enthalpy:                                             100 J/g         99.1 J/g                                             Low melting                                                                            1st peak at 57° C.                                                                     1st peak at 54° C.                            form     (very weak)     (very weak;                                                   2nd peak at 78° C.                                                                     endothermic)                                                  (weak)          2nd endothermic peak                                          3rd endothermic peak                                                                          at 104° C.                                             at 107° C.;                                                                            melting temperature                                           melting enthalpy:                                                                             102° C.                                                55 J/g          52 J/g                                                        4th endothermic peak                                                                          3rd exothermic path                                           at 132° C.                                                                             of the base line by                                           melting enthalpy:                                                                             crystallisation of                                            25 J/g          the substance melting                                                         at 104° C.                                                             4th endothermic peak                                                          at 131° C., melting                                                    temperature 130° C.                                                    melting enthalpy                                                              52 J/g                                               ______________________________________                                    

EXAMPLE 4 Ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

0.79 g (1.65 mMol) of ethyl(Z)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl]-benzoate,melting point 124°-127° C., are dissolved in 10 ml of degassed solventmixture (methanol/methylene chloride=5/1) under an Argon atmosphere andadded to a solution of 17 mg of the NOYORI-catalyst Ru(O-acetyl)₂[(S)-BINAP] (prepared from [Ru(COD)Cl₂ ]_(n) with (S)-BINAP[=(S)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl], triethylamine andsodium acetate) and 3 mg of titanium tetraisopropoxide in 10 ml ofdegassed solvent mixture (methanol/methylene chloride =5/1). Thereaction mixture is drawn into an autoclave evacuated at 10⁻² mbar. Thisis flushed five times with hydrogen at 5 bar and finally hydrogenated at30° C. and 100 bar until the hydrogen uptake has ceased (154 hours). Thereddish-brown solution is evaporated down in vacuo, the evaporationresidue is dissolved in 80 ml of ether, filtered off from theundissolved brown flakes by means of activated charcoal and theresulting clear, bright yellow filtrate is evaporated down in vacuo. Theevaporation residue (0.60 g) is refluxed in 60 ml of n-hexane andfiltered hot to separate it from the insoluble matter. The filtrate isleft to stand overnight at ambient temperature. The crystals which areprecipitated are filtered off.

Yield: 0.45 g (56.7% of theory),

Melting point: 131°-133° C. (after sintering from 120° C.)

Enantiomeric purity: ee=39% (S) [HPLC method: see Example 1].

EXAMPLE 5 Ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

0.05 g (1.15 mMol) of 55% sodium hydride in oil are added to a solutionof 0.68 g (1.15 mMol) of ethyl(S)-2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate[melting point: 125°-126° C.; [α]_(D) ²⁰ =+12.87° (c=1.01 in methanol)]in 5 ml of anhydrous dimethylformamide and the mixture is stirred for0.5 hours at ambient temperature. Then a solution of 0.12 ml (1.15 mMol)of ethyliodide in 2.5 ml of anhydrous dimethylformamide is addeddropwise thereto and the mixture is stirred for 5 hours at ambienttemperature. It is evaporated down in vacuo, the residue is distributedbetween dilute sodium hydroxide solution and chloroform, the organicextract is dried, filtered and evaporated down in vacuo. The evaporationresidue is purified by column chromatography on silica gel(toluene/ethyl acetate=10/1).

Yield: 0.48 g (67% of theory),

Melting point: 110°-112° C.

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.61; H 8.54; N 5.97.

Enantiomeric purity: ee=98.5% (S) [HPLC method: see Example 1].

EXAMPLE 6 Ethyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

Prepared from(S)-2-hydroxy-4-[N-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid analogously to Example 5 using 2 equivalents of sodium hydride and2 equivalents of ethyl iodide.

Yield: 42% of theory,

Melting point: 110°-112° C.

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.61; H 8.54; N 5.99.

Enantiomeric purity: ee=98.3% [HPLC method: see Example 1].

EXAMPLE 7 Ethyl(S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoateand Ethyl(R)(-)-3-ethoxy-4-[N-(1-(2-piperidino-phenyl)-2-methyl-1-butyl)-aminocarbonylmethyl]-benzoate

920 mg of ethyl(±)-2-ethoxy-4-[N-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoateare separated, in single doses of 10 mg, on a preparative chiral phaseHPLC column made by Baker, in which (S)-N-3,5-dinitrobenzoyl-leucine iscovalently bonded to aminopropyl-silica gel (particle size: 40 μm;column length: 250 mm with an internal diameter of 20 mm; eluant:n-hexane/tetrahydrofuran/ethanol/methylene chloride (180/20/3/2); flowrate: 21.25 ml per minute; temperature: 27° C.; UV-detection at 285 nm),in which first the (R)(-)-enantiomer (peak 1) and then the(S)(+)-enantiomer (peak 2) is eluted. After evaporation in vacuo, thefollowing are obtained from the correspondingly cut and collectedfractions:

Peak 1 fraction (R): 423 mg (crude),

Peak 2 fraction (S): 325 mg (crude).

In order to remove any impurities (including the stabiliser2,6-di-tert.butyl-4-methyl-phenol contained in the tetrahydrofuran) thetwo fractions are each purified by column chromatography on silica gel(toluene/acetone=10/1).

(R)(-)-enantiomer

Yield: 234.5 mg (51% of theory),

Melting point: 122°-124° C. (petroleum ether+acetone)

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.40; H 8.18; N 5.71.

[α]_(D) ²⁰ =-8.3° (c=1 in methanol)

(S)-enantiomer

Yield: 131.2 mg (28.5% of theory),

Melting point: 122°-124° C. (petroleum ether/acetone=8/1)

Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.28; H 8.44; N 5.70.

[α]_(D) ²⁰ =+8.3° (c=1 in methanol)

A chiral cell OD column made by Daicel is also suitable for separatingthe enantiomers. The (R)-enantiomer is eluted after 6.8 minutes and the(S)-enantiomer after 8.5 minutes on a column 250 mm long with aninternal diameter of 4.6 mm (eluant: absolute ethanol/(n-hexane+0.2%diethylamine)=5/95; temperature: 40° C.; UV-detection at 245 nm).

EXAMPLE 8(R)(-)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid ×0.4 H₂ O

Prepared from 150 mg (0.312 mMol) of ethyl(R)(-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-amiocarbonyl-methyl]-benzoate[melting point: 122°-124° C.;

[α]_(D) ²⁰ =-8.3° (c=1 in methanol)] by saponification with 1N sodiumhydroxide solution in ethanol analogously to Example 3.

Yield: 95.8 mg (66.7% of theory),

Melting point: 103°-105° C. (toluene/petroleum ether)

Calc. (×0.4 H₂ O): C 70.51; H 8.01; N 6.09. Found: C 70.88; H 7.79; N5.81.

Molecular peak M⁺ : Calculated: 452 Found: 452

[α]_(D) ²⁰ =-6.5° (c=1 in methanol)

Enantiomeric purity: ee=99.7% (R) [HPLC method: see Example 3].

EXAMPLE 9(S)(+)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid ×0.4 H₂ O

Prepared from 89 mg (0.198 mMol) of ethyl(S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate[melting point: 122°-124° C.; [α]_(D) ²⁰ =+8.3° (c=1 in methanol)] bysaponification with 1sodium hydroxide solution in ethanol analogously toExample 3.

Yield: 44.5 mg (48.8% of theory),

Melting point: 102°-103° C. (toluene/petroleum ether)

Calc.: (×0.4 H₂ O) C 70.51; H 8.01. Found: C 70.80; H 8.06.

[α]_(D) ²⁰ =+6.7° (c=1 in methanol)

Enantiomeric purity: ee=99.6% (S) [HPLC method: see Example 3].

EXAMPLE 10(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid

0.26 g (0.47 mMol) of benzyl(S)-2-ethoxy-4-[N-(1-(2-pipieridino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate(melting point: 91°-92° C.; [α]_(D) ²⁰ =+9.5°; c=1.05 in methanol) arehydrogenated in 10 ml of ethanol using 0.12 g of (10%)palladium/charcoal at 50° C. and 5 bar of hydrogen. After 5 hours thecatalyst is filtered off over keiselguhr and evaporated down in vacuo.The evaporation residue is crystallised from ethanol/water (2/1).

Yield: 0.15 g (70% of theory),

Melting point: 130°-131° C.

Calculated: C 71.64; H 8.02; N 6.19. Found: C 71.76; H 8.12; N 6.05.

Enantiomeric purity: ee=99.6% [HPLC method: see Example 3].

EXAMPLE 11(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid

102 mg (0.20 mMol) of tert.butyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate(melting point: 122°-123° C.; [α]_(D) ²⁰ =+8.7°; c=1 in methanol) arerefluxed in 5 ml of benzene together with a few crystals ofp-toluenesulphonic acid hydrate, for half a day. The desired product isthen obtained, according to thin layer chromatography, according to theR_(F) value and mass spectrum.

Melting point: 129°-131° C.

Molecular peak M⁺ : Calc.: 452 Found: 452

EXAMPLE 12(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoicacid

200 mg (0.395 mMol) of tert.butyl(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate(melting point: 122°-123° C.; [α]_(D) ²⁰ =+8.7°; c=1 in methanol) arestirred into 2 ml of methylene chloride together with 0.45 g (3.95 mMol)of trifluoroacetic acid overnight at ambient temperature. The mixture isevaporated down in vacuo and the evaporation residue is distributedbetween aqueous sodium hydrogen carbonate solution and ethyl acetate.The organic extract is dried, filtered and evaporated down in vacuo. Theevaporation residue is crystallised from ethanol/water (2/1).

Yield: 115 mg (64.7% of theory),

Melting point: 126°-128° C.

Calculated: C 71.64; H 8.02; N 6.19. Found: C 71.39; H 7.91; N 6.06.

[α]_(D) ²⁰ =+6.97° (c=0.975 in methanol)

Enantiomeric purity: ee=99.8% [HPLC method: see Example 3].

EXAMPLE 13 Tablets containing 0.25 mg AG-EE 623 ZW

One tablet contains:

0.250 mg of active substance

0.125 mg of N-methylglucamine

0.038 mg of polyvinylpyrrolidone

0.075 mg of polyoxyethylenepolyoxypyropylene polymer

0.150 mg of microcrystalline cellulose

Preparation

The active substance and excipients are dissolved in water at 90° C. orthe microcrystalline cellulose is suspended and the dispersion isevaporated down in vacuo. The dry mass is screened to a mesh size of 1mm.

The following ingredients are added to the granulated active substance,for each tablet;

    ______________________________________                                        24.862 mg    of sodium carboxymethyl starch                                   24.000 mg    of microcrystalline cellulose                                     0.500 mg    of magnesium stearate                                            50.000 mg                                                                     ______________________________________                                    

Round, biplanar tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture.

EXAMPLE 14 Tablets containing 0.5 mg of AG-EE 623 ZW

One tablet contains:

0.500 mg of active substance

0.250 mg of N-methylglucamine

0.075 mg of polyvinylpyrrolidone

0.150 mg of polyoxyethylenepolyoxypropylene polymer

0.300 mg of microcrystalline cellulose

Preparation

The active substance and excipients are dissolved in water at 90° C. andthe microcrystalline cellulose is suspended therein and the dispersionis evaporated down in vacuo. The dry mass is screened to a mesh size of1 mm.

The following ingredients are added to the active substance granules foreach tablet:

    ______________________________________                                        24.225 mg    of sodium carboxymethyl starch                                   24.000 mg    of microcrystalline cellulose                                     0.500 mg    of magnesium stearate                                            50.000 mg                                                                     ______________________________________                                    

Round, biplanar tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture.

EXAMPLE 15 Tablets containing 1.0 mg of AG-EE 623 ZW

One tablet contains:

1.00 mg of active substance

0.50 mg of N-methylglucamine

0.15 mg of polyvinylpyrrolidone

0.03 mg of polyoxyethylenepolyoxypropylene polymer

0.60 mg of microcrystalline cellulose

Preparation

The active substance and excipients are dissolved in water at 90° C. andthe microcrystalline cellulose is suspended therein and the dispersionis evaporated down in vacuo. The dry mass is screened to a mesh size of1 mm.

The following ingredients are added to the granulated active substancefor each tablet:

    ______________________________________                                        23.22 mg    of sodium carboxymethyl starch                                    24.00 mg    of microcrystalline cellulose                                      0.50 mg    of magnesium stearate                                             50.00 mg                                                                      ______________________________________                                    

Round, biplanar tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture.

EXAMPLE 16 Tablets containing 1.5 mg of AG-EE 623 ZW

One tablet contains:

1.500 mg of active substance

0.750 mg of N-methylglucamine

0.225 mg of polyvinylpyrrolidone

0.045 mg of polyoxyethylenepolyoxypropylene polymer

0.900 mg of microcrystalline cellulose

Preparation

The active substance and excipients are dissolved in water at 90° C. andthe microcrystalline cellulose is suspended therein and the dispersionis evaporated down in vacuo. The dry mass is screened to a mesh size of1 mm.

The following ingredients are added to the granulated active substancefor each tablet:

    ______________________________________                                        23.080 mg    of sodium carboxymethyl starch                                   23.000 mg    of microcrystalline cellulose                                     0.500 mg    of magnesium stearate                                            50.000 mg                                                                     ______________________________________                                    

Round, biplanar tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture.

EXAMPLE 17 Tablets containing 2.0 mg of AG-EE 623 ZW

One tablet contains:

2.00 mg of active substance

1.00 mg of L-lysine

1.00 mg of polyvinylpyrrolidone

1.00 mg of polyoxyethylenepolyoxypropylene polymer

4.00 mg of microcrystalline cellulose

Preparation

The ingredients are dissolved in water at 90° C. and themicrocrystalline cellulose is suspended therein and the dispersion isprocessed in a spray dryer. The following ingredients are then added foreach tablet.

    ______________________________________                                        20.35 mg    of microcrystalline cellulose                                     20.00 mg    of sodium carboxymethyl starch                                     0.65 mg    of magnesium stearate                                             50.00 mg                                                                      ______________________________________                                    

Round, biconvex tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture and are given a flavour-masking coatingof hydroxypropymethylcellulose.

EXAMPLE 18 Tablets containing 2.5 mg of AG-EE 623 ZW

One tablet contains:

2.50 mg of active substance

1.25 mg of L-lysine

1.25 mg of polyvinylpyrrolidone

1.25 mg of polyoxyethylenepolyoxypropylene polymer

4.10 mg of microcrystalline cellulose

Preparation

The ingredients are dissolved in water at 90° C. and themicrocrystalline cellulose is suspended therein and the dispersion isprocessed in a spray dryer. Then the following ingredients are added foreach tablet:

    ______________________________________                                        19.50 mg    of microcrystalline cellulose                                     19.50 mg    of sodium carboxymethyl starch                                     0.65 mg    of magnesium stearate                                             50.00 mg                                                                      ______________________________________                                    

Round, biconvex tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture and given a flavour-masking coating ofhydroxypropylmethyl cellulose.

EXAMPLE 19 Tablets containing 3.0 mg of AG-EE 623 ZW

One tablet contains:

3.0 mg of active substance

1.5 mg of L-lysine

1.5 mg of polyvinylpyrrolidone

1.5 mg of polyoxyethylenepolyoxypropylene polymer

Preparation

The ingredients are dissolved in water at 90° C. and the solution isprocessed in a spray dryer. Then, for each tablet, the followingingredients are added:

    ______________________________________                                        21.5 mg     of microcrystalline cellulose                                     21.0 mg     of sodium carboxymethyl starch                                    50.0 mg                                                                       ______________________________________                                    

Round, biconvex tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture and given a flavour-masking coating ofhydroxypropylmethyl cellulose.

EXAMPLE 20 Tablets containing 5 mg of AG-EE 623 ZW

One tablet contains:

5.0 mg of active substance

2.5 mg of L-lysine

2.5 mg of polyvinylpyrrolidone

2.5 mg of polyoxyethylenepolyoxypropylene polymer

Preparation

The ingredients are dissolved in water at 90° C. and the solution isprocessed in a spray dryer. Then, for each tablet, the followingingredients are added:

    ______________________________________                                        19.0 mg     of microcrystalline cellulose                                     18.5 mg     of sodium carboxymethyl starch                                    50.0 mg                                                                       ______________________________________                                    

Round, biconvex tablets weighing 50 mg and measuring 5 mm in diameterare compressed from this mixture and given a flavour-masking coating ofhydroxypropylmethyl cellulose.

What is claimed is:
 1. A method of lowering the level of glucose in theblood of a warm-blooded animal and humans in need thereof, whichcomprises orally or parenterally administering to said animal and humansan effective hypoglycemic amount of a compound of formula ##STR30##wherein R₁ represents an unbranched alkyleneimino group with 4 to 6carbon atoms optionally mono- or di-(alkyl of 1 to 3 carbonatoms)-substituted;R₂ represents a hydrogen or halogen atom or a methylor methoxy group; R₃ represents a hydrogen atom, an alkyl group with 1to 7 carbon atoms, a phenyl group optionally substituted by a halogenatom or a methyl or methoxy group, an alkyl group with 1 or 2 carbonatoms substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahydrofuranyl,tetrahydropyranyl, cycloalkyl or phenyl group, in which the alkoxy partcan contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2or 3 carbon atoms and the cycloalkyl part can contain 3 to 7 carbonatoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with3 to 5 carbon atoms, a carboxy group or an alkoxycarbonyl group with atotal or 2 to 5 carbon atoms; R₄ represents a hydrogen atom, a methyl,ethyl or allyl group; and W represents a methyl, hydroxymethyl, formyl,carboxyl, alkoxycarbonyl, cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl,carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylmethyl,2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, in which eachalkoxy part can contain from 1 to 4 carbon atoms and can be substitutedby a phenyl group; and when R₃ is other then hydrogen and/or the radicalR₁ contains an optically active carbon atom, the enantiomers and thediastereomers thereof or their mixtures; when W is carboxyl, a non-toxicsalt thereof formed with an inorganic or organic base; or a non-toxicacid addition salt thereof formed by an inorganic or organic acid withthe amino function in the R₁ -position.
 2. A compound of formula##STR31## wherein W' represents a carboxy group or an alkoxycarbonylgroup having a total of 2 to 5 carbon atoms, wherein the alkyl moiety ofthe alkoxy group may be substituted by a phenyl group and the additionsalts thereof.